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高分SCI文摘

2021年

No.1

发布时间:2021-01-12 浏览次数:
字号: + - 14

Medical Abstracts

Filters applied: from 2021/1/1 - 2021/1/12

1. Nat Commun. 2021 Jan 8;12(1):143. doi: 10.1038/s41467-020-20224-x.

Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.

Mendes V(1), Green SR(2), Evans JC(3), Hess J(4), Blaszczyk M(5), Spry C(4),

Bryant O(5), Cory-Wright J(5), Chan DS(4), Torres PHM(5), Wang Z(6), Nahiyaan

N(6), O'Neill S(2), Damerow S(2), Post J(2), Bayliss T(2), Lynch SL(3), Coyne

AG(4), Ray PC(2), Abell C(4), Rhee KY(6), Boshoff HIM(7), Barry CE 3rd(3)(7),

Mizrahi V(3), Wyatt PG(2), Blundell TL(8).

Author information:

(1)Department of Biochemistry, University of Cambridge, 80 Tennis Court Road,

Cambridge, CB2 1GA, UK. vgm23@cam.ac.uk.

(2)Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow

Street, Dundee, DD1 5EH, Scotland, UK.

(3)MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of

Excellence for Biomedical TB Research & Wellcome Centre for Infectious Diseases

Research in Africa, Institute of Infectious Disease and Molecular Medicine and

Department of Pathology, Faculty of Health Sciences, University of Cape Town,

Anzio Road, Observatory 7925, Cape Town, South Africa.

Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous

metabolic pathways and cellular processes, and its biosynthetic pathway has

raised substantial interest as a drug target against multiple pathogens

including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in

five steps, with the second and third steps being catalysed in the vast majority

of prokaryotes, including M. tuberculosis, by a single bifunctional protein,

CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here

we report the first structure of a full-length CoaBC, from the model organism

Mycobacterium smegmatis, describe how it is organised as a dodecamer and

regulated by CoA thioesters. A high-throughput biochemical screen focusing on

CoaB identified two inhibitors with different chemical scaffolds. Hit expansion

led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB,

which we show to bind to a cryptic allosteric site within CoaB.

DOI: 10.1038/s41467-020-20224-x

PMID: 33420031

2. Clin Microbiol Infect. 2021 Jan 6:S1198-743X(20)30780-1. doi:

10.1016/j.cmi.2020.12.020. Online ahead of print.

Detection of Mycobacterium tuberculosis complex in pulmonary and extrapulmonary

samples with the FluoroType MTBDR assay.

Svensson E(1), Folkvardsen DB(2), Rasmussen EM(2), Lillebaek T(3).

Author information:

(1)International Reference Laboratory of Mycobacteriology, Statens Serum

Institut, 2300 Copenhagen, Denmark. Electronic address: esn@ssi.dk.

(2)International Reference Laboratory of Mycobacteriology, Statens Serum

Institut, 2300 Copenhagen, Denmark.

(3)International Reference Laboratory of Mycobacteriology, Statens Serum

Institut, 2300 Copenhagen, Denmark; Global Health Section, Department of Public

Health, University of Copenhagen, 1014 Copenhagen, Denmark.

OBJECTIVES: Rifampicin (RIF) and isoniazid (INH) are the two most effective

first-line antibiotic drugs for the treatment of tuberculosis (TB). The new

FluoroType MTBDR (FT-MTBDR) real-time PCR is intended to detect INH and RIF

resistance mutations as a second step following a primary Mycobacterium

tuberculosis complex (MTBC) PCR. Here we evaluate the feasibility of the

FT-MTBDR assay to detect simultaneously MTBC specific DNA as well as to detect

potential INH and RIF resistance through analysing inhA promotor, katG and rpoB

sequences in one PCR reaction.

METHODS: We analysed 3,885 consecutive primary samples with FT-MTBDR and

compared the results with microscopy and culture: 978 were from sputum, 2,007

from other respiratory tract locations plus gastric lavages, and 875 from

extrapulmonary locations, respectively.

RESULTS: Overall, 176 samples were MTBC culture positive and 139 FT-MTBDR

positive, providing a FT-MTBDR sensitivity of 0.714 (95% confidence interval

0.640 - 0.779) and specificity of 0,996 (0.994 -0.998), respectively. For the

978 sputum, 96 were MTBC culture positive and 89 FT MTBDR positive, sensitivity

0.854 (0.764 - 0.915) and specificity 0.992 (0.983 - 0.997). Of the 139 MTBC

positive, 99 (71%) had interpretable genotypic resistance results for at least

one drug, 92 (66%) for both drugs.

CONCLUSIONS: The ability of FT-MTBDR to detect MTBC is adequate with the

significant added feature of simultaneous genotypic resistance detection of both

INH and RIF in a single PCR reaction.

Copyright © 2021 European Society of Clinical Microbiology and Infectious

Diseases. Published by Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.cmi.2020.12.020

PMID: 33421581

3. Clin Microbiol Infect. 2021 Jan 6:S1198-743X(20)30791-6. doi:

10.1016/j.cmi.2020.12.031. Online ahead of print.

Patient pathway analysis of tuberculosis diagnostic delay: a multicentre

retrospective cohort study in China.

Zhang L(1), Weng TP(1), Wang HY(1), Sun F(1), Liu YY(1), Lin K(1), Zhou Z(1),

Chen YY(2), Li YG(3), Chen JW(4), Han LJ(5), Liu HM(6), Huang FL(7), Cai C(8),

Yu HY(9), Tang W(10), Huang ZH(11), Wang LZ(12), Bao L(13), Ren PF(14), Deng

GF(15), Lv JN(16), Pu YL(17), Xia F(18), Li T(19), Deng Q(20), He GQ(21), Li

Y(22), Zhang WH(23).

Author information:

(1)Department of Infectious Diseases, Huashan Hospital, Fudan University,

Shanghai, China.

(2)Department of Tuberculosis, Hangzhou Red Cross Hospital, Hangzhou, China.

(3)Department of Infectious Diseases, The First Affiliated Hospital, Harbin

Medical University, Harbin, China.

OBJECTIVES: Diagnostic delay of tuberculosis (TB) is an important but

underappreciated problem. Our study aimed to analyse the patient pathway and

possible risk factors of the long diagnostic delay (LDD).

METHODS: We enrolled 400 new bacteriologically diagnosed patients with pulmonary

TB from 20 hospitals across China. LDD was defined as the interval between the

initial-care-visit and the diagnosis confirmation exceeding 14 days. Its

potential risk factors were investigated by multivariate logistic regression and

multilevel logistic regression. Hospitals in China were classified by increasing

size, from level 0 to 3. TB laboratory equipment in hospitals were also

evaluated.

RESULTS: The median diagnostic delay was 20 days (IQR: 7-72 days), and 229 of

400 patients (57.3%, 95% CI 52.4-62.1) had LDD. Fifteen percent of participants

were diagnosed at the initial-care-visit. Compared to level 0 facilities,

choosing level 2 (OR 0.27, 95% CI 0.12-0.62, p = 0.002) and level 3 facilities

(OR 0.34, 95% CI 0.14-0.84, p = 0.019) for the initial-care-visit was

independently associated with less LDD. Equipping with smear, culture, and Xpert

at intial-care-visit simultaneously also helped avoiding LDD. (OR 0.28, 95% CI

0.09-0.82, p = 0.020). The multilevel logistic regression yielded similar

results. Availability of smear, culture, and Xpert was lower in level 0-1

facilities than in level 2-3 facilities (p<0.001, respectively).

CONCLUSIONS: Most patients failed to be diagnosed at the initial-care-visit.

Patients who went to low-level facilities initially had a higher risk of LDD.

Improving TB laboratory equipment especially at low-level facilities is urgently

needed.

Copyright © 2020. Published by Elsevier Ltd.

DOI: 10.1016/j.cmi.2020.12.031

PMID: 33421578

4. Int J Biol Macromol. 2021 Jan 6;171:82-88. doi: 10.1016/j.ijbiomac.2020.12.179.

Online ahead of print.

High-yield production of major T-cell ESAT6-CFP10 fusion antigen of M.

tuberculosis complex employing codon-optimized synthetic gene.

Gutiérrez-Ortega A(1), Moreno DA(1), Ferrari SA(1), Espinosa-Andrews H(1), Ortíz

EP(2), Milián-Suazo F(3), Alvarez AH(4).

Author information:

(1)Centro de Investigación y Asistencia en Tecnología y diseño del Estado de

Jalisco A.C., Av. Normalistas 800, C.P. 44270 Guadalajara, Mexico.

(2)Centro Universitario de Los Altos, Universidad de Guadalajara, Km 7.5

Carretera a Yahualica, CP 47600 Tepatitlán de Morelos, Mexico.

(3)Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. de las

Ciencias s/n Juriquilla, Delegación Santa Rosa Jáuregui, C.P. 76230 Querétaro,

Mexico.

Translation engineering and bioinformatics have accelerated the rate at which

gene sequences can be improved to generate multi-epitope proteins. Strong

antigenic proteins for tuberculosis diagnosis include individual ESAT6 and CFP10

proteins or derived peptides. Obtention of heterologous multi-component antigens

in E. coli without forming inclusion bodies remain a biotechnological challenge.

The gene sequence for ESAT6-CFP10 fusion antigen was optimized by codon bias

adjust for high-level expression as a soluble protein. The obtained fusion

protein of 23.7 kDa was observed by SDS-PAGE and Western blot analysis after

Ni-affinity chromatography and the yield of expressed soluble protein reached a

concentration of approximately 67 mg/L in shake flask culture after IPTG

induction. Antigenicity was evaluated at 4 μg/mL in whole blood cultures from

bovines, and protein stimuli were assessed using a specific in vitro IFN-γ

release assay. The hybrid protein was able to stimulate T-cell specific

responses of bovine TB suspects. The results indicate that improved E. coli

codon usage is a good and cost-effective strategy to potentialize large scale

production of multi-epitope proteins with sustained antigenic properties for

diagnostic purposes.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

DOI: 10.1016/j.ijbiomac.2020.12.179

PMID: 33418045

5. Eur Respir Rev. 2021 Jan 6;30(159):200260. doi: 10.1183/16000617.0260-2020.

Print 2021 Mar 31.

Impact of latent tuberculosis infection on health and wellbeing: a systematic

review and meta-analysis.

Wong YJ(1), Noordin NM(2), Keshavjee S(3), Lee SWH(4)(5)(6)(7).

Author information:

(1)School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia.

(2)National Public Health Laboratory, Ministry of Health, Sungai Buloh,

Malaysia.

(3)Dept of Global Health and Social Medicine, Harvard Medical School, Harvard

University, Boston, MA, USA.

The impact of latent tuberculosis infection (LTBI) on health and wellbeing is

not well understood. This review aims to evaluate the health and wellbeing of

individuals with LTBI. A systematic literature search was performed to assess

studies reporting patient-reported outcomes in LTBI management including

health-related quality of life (HRQoL), health utilities, disease burden and

experience of individuals with LTBI. A pooled analysis was performed to estimate

the effect of LTBI on HRQoL.A total of 4464 studies were screened, of which 13

eligible articles describing nine unique studies were included for review. The

HRQoL of individuals with LTBI and without tuberculosis (TB) infection were

comparable, and better than patients with active TB disease. However,

individuals with LTBI reported poorer mental health compared with individuals

without TB infection (mean difference -4.16, 95% CI -7.45--0.87; p=0.01).

Qualitative studies suggest the presence of fear, anxiety and stigma in

individuals with LTBI.This review highlights potential psychosocial challenges

in individuals with LTBI despite the absence of clinical symptoms. While their

quality of life was marginally affected, this could be evidence to support LTBI

management in preventing TB re-activation and the severe consequences of active

TB disease that affect all domains of HRQoL.

Copyright ©ERS 2021.

DOI: 10.1183/16000617.0260-2020

PMID: 33408089

6. Am J Respir Crit Care Med. 2021 Jan 6. doi: 10.1164/rccm.202007-2686OC. Online

ahead of print.

Antigen-specific T Cell Activation Distinguishes Between Recent and Remote

Tuberculosis Infection.

Mpande CAM(1), Musvosvi M(1), Rozot V(1), Mosito B(1), Reid TD(1), Schreuder

C(1), Lloyd T(1), Bilek N(1), Huang H(2), Obermoser G(2), Davis MM(2), Ruhwald

M(3)(4), Hatherill M(1), Scriba TJ(1), Nemes E(5); ACS Study Team.

Author information:

(1)University of Cape Town, 37716, South African Tuberculosis Vaccine

Initiative, Institute of Infectious Disease and Molecular Medicine, Division of

Immunology, Department of Pathology, , Cape Town, South Africa.

(2)Stanford University School of Medicine, 10624, Institute for Immunity,

Transplantation and Infection, , Stanford, California, United States.

(3)Statens Serum Institut, 4326, Copenhagen , Denmark.

RATIONALE: Current diagnostic tests fail to identify individuals at higher risk

of progression to tuberculosis disease, such as those with recent Mycobacterium

tuberculosis infection, who should be prioritized for targeted preventive

treatment.

OBJECTIVES: To define a blood-based biomarker, measured with a simple flow

cytometry assay, that can stratify different stages of tuberculosis infection to

infer risk of disease.

METHODS: South African adolescents were serially tested with QuantiFERON-TB Gold

to define recent (QuantiFERON-TB conversion<6 months) and persistent

(QuantiFERON-TB+ for >1 year) infection. We defined the ΔHLA-DR median

fluorescence intensity biomarker as the difference in HLA-DR expression between

IFN-γ+TNF+ Mycobacterium tuberculosis-specific and total CD3+ T cells. Biomarker

performance was assessed by blinded prediction in untouched test cohorts with

recent versus persistent infection or tuberculosis disease, and unblinded

analysis of asymptomatic adolescents with tuberculosis infection who remained

healthy (non-progressors) or who progressed to microbiologically-confirmed

disease (progressors).

MEASUREMENTS AND MAIN RESULTS: In the test cohorts, frequencies of Mycobacterium

tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n=25) and

QuantiFERON-TB+ (n=47) individuals (area under the ROC curve and 95% confidence

intervals: 0.94; 0.87-1.00). ΔHLA-DR significantly discriminated between recent

(n=20) and persistent (n=22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent

QuantiFERON-TB+ and newly diagnosed tuberculosis (n=19, 0.99; 0.96-1.00); and

tuberculosis progressors (n=22) and non-progressors (n=34, 0.75; 0.63-0.87).

However, ΔHLA-DR MFI could not discriminate between recent QuantiFERON-TB+ and

tuberculosis (0.67; 0.50-0.84).

CONCLUSION: The ΔHLA-DR biomarker can identify individuals with recent

QuantiFERON-TB conversion and those with disease progression, allowing targeted

provision of preventive treatment to those at highest risk of tuberculosis.

Further validation studies of this novel immune biomarker in various settings

and populations at risk are warranted.

DOI: 10.1164/rccm.202007-2686OC

PMID: 33406011

7. J Travel Med. 2021 Jan 6;28(1):taaa214. doi: 10.1093/jtm/taaa214.

Risk of latent and active tuberculosis infection in travellers: a systematic

review and meta-analysis.

Diefenbach-Elstob TR(1)(2), Alabdulkarim B(3), Deb-Rinker P(4), Pernica JM(5),

Schwarzer G(6), Menzies D(7)(8)(9), Shrier I(1)(10), Schwartzman K(7)(8)(9),

Greenaway C(1)(2)(11).

Author information:

(1)Centre for Clinical Epidemiology, Lady Davis Institute, 3755 Côte

Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada.

(2)Department of Medicine, McGill University, 1001 Decarie Boulevard, Suite

D05-2212, Montreal, Quebec H4A 3J1, Canada.

(3)Department of Internal Medicine, McGill University, 1001 Decarie Boulevard,

Rm D05.5840, Montreal, Quebec H4A 3J1, Canada.

INTRODUCTION: Achieving tuberculosis (TB) elimination in low TB incidence

countries requires identification and treatment of individuals at risk for

latent TB infection (LTBI). Persons travelling to high TB incidence countries

are potentially at risk for TB exposure. This systematic review and

meta-analysis estimates incident LTBI and active TB among individuals travelling

from low to higher TB incidence countries.

METHODS: Five electronic databases were searched from inception to 18 February

2020. We identified incident LTBI and active TB among individuals travelling

from low (<10 cases/100000 population) to intermediate (10-100/100000) or high

(>100/100000) TB incidence countries. We conducted a meta-analysis and

meta-regression using a random effects model of log-transformed proportions

(cumulative incidence). Subgroup analyses investigated the impact of travel

duration, travel purpose and TB incidence in the destination country.

RESULTS: Our search identified 799 studies, 120 underwent full-text review, and

10 studies were included. These studies included 1154673 travellers observed

between 1994 and 2013, comprising 443 health care workers (HCW), 1068636

military personnel and 85594 general travellers/volunteers. We did not identify

any studies that estimated incidence of LTBI or active TB among people

travelling to visit friends and relatives (VFRs). The overall cumulative

incidence of LTBI was 2.3%, with considerable heterogeneity. Among individuals

travelling for a mean/median of up to 6 months, HCWs had the highest cumulative

incidence of LTBI (4.3%), whereas the risk was lower for military (2.5%) and

general travellers/volunteers (1.6%). Meta-regression did not identify a

difference in incident LTBI based on travel duration and TB incidence in the

destination country. Five studies reported cases of active TB, with an overall

pooled estimate of 120.7 cases per 100000 travellers.

CONCLUSIONS: We found that travelling HCWs were at highest risk of developing

LTBI. Individual risk activities and travel purpose were most associated with

risk of TB infection acquired during travel.

© International Society of Travel Medicine 2020. All rights reserved. For

Permissions, please e-mail: journals.permissions@oup.com.

DOI: 10.1093/jtm/taaa214

PMID: 33225357

8. Int J Biol Macromol. 2021 Jan 5;171:59-73. doi: 10.1016/j.ijbiomac.2020.12.182.

Online ahead of print.

Essential biochemical, biophysical and computational inputs on efficient

functioning of Mycobacterium tuberculosis H(37)Rv FtsY.

Shivangi(1), Ekka MK(1), Meena LS(2).

Author information:

(1)CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007,

India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC,

Ghaziabad, Uttar Pradesh 201 002, India.

(2)CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007,

India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC,

Ghaziabad, Uttar Pradesh 201 002, India. Electronic address: meena@igib.res.in.

Mycobacterium tuberculosis (M. tuberculosis H37Rv) utilizes the signal

recognition particle pathway (SRP pathway) system for secretion of various

proteins from ribosomes to the extracellular surface which plays an important

role in the machinery running inside the bacterium. This system comprises of

three major components FtsY, FfH and 4.5S rRNA. This manuscript highlights

essential factors responsible for the optimized enzymatic activity of FtsY.

Kinetic parameters include Vmax and Km for the hydrolysis of GTP by ftsY which

were 20.25±5.16 μM/min/mg and 39.95±7.7 μM respectively. kcat and catalytic

efficiency of the reaction were 0.012±0.003 s-1 and 0.00047±0.0001 μM/s-1

respectively. These values were affected upon changing the standard conditions.

Cations (Mg2+ and Mn2+) play important role in FtsY enzymatic activity as

increasing Mg2+ decrease the activity. Mn2+on the other hand is required at

higher concentration around 60 mM for carrying optimum GTPase activity. FtsY is

hydrolyzing ATP and GDP as well and GDP acts as an inhibitor of the reaction. MD

simulation shows effective binding and stabilization of the FtsY complexed

structure with GTP, GDP and ATP. Mutational analysis was done at two important

residues of GTP binding motif of FtsY, namely, GXXXXGK (K236) and DXXG (D367)

and showed that these mutations significantly decrease FtsY GTPase activity.

FtsY is comprised of α helices, but this structural pattern was shown to change

with increasing concentrations of GTP and ATP which symbolize that these ligands

cause significant conformational change by variating the secondary structure to

transduce signals required by downstream effectors. This binding favors the

functional stabilization of FtsY by destabilization of α-helix integrity.

Revealing the hidden aspects of the functioning of FtsY might be an essential

part for the understanding of the SRP pathway which is one of the important

contributors of M. tuberculosis virulence.

Copyright © 2020 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.ijbiomac.2020.12.182

PMID: 33412199

9. Int J Biol Macromol. 2021 Jan 5;171:28-36. doi: 10.1016/j.ijbiomac.2020.12.191.

Online ahead of print.

Structural studies on Mycobacterium tuberculosis HddA enzyme using small angle

X-ray scattering and dynamics simulation techniques.

Karan S(1), Behl A(1), Sagar A(2), Bandyopadhyay A(1), Saxena AK(3).

Author information:

(1)Rm-403/440, Structural Biology Lab, School of Life Sciences, Jawaharlal Nehru

University, New Delhi 110067, India.

(2)Center de Biochimie Structurale, Montpellier 34090, France.

(3)Rm-403/440, Structural Biology Lab, School of Life Sciences, Jawaharlal Nehru

University, New Delhi 110067, India. Electronic address:

ajaysaxena@mail.jnu.ac.in.

Mycobacterium tuberculosis HddA enzyme phosphorylates the M7P substrate and

converts it to M7PP product in GDP-D-α-D-heptose biosynthetic pathway. For

structural and functional studies on MtbHddA, we have purified the enzyme, which

eluted as a monomer from size exclusion column. Purified MtbHddA had ATPase

activity. The SAXS analysis supported globular monomeric scattering profile of

MtbHddA in solution. The CD analysis showed that MtbHddA contains 45% α-helix,

18% β-stands, and 32% random coil structures and showed unfolding temperature

(TM) ~ 47.5 °C. The unfolding temperature of MtbHddA is enhanced by 1.78±0.41 °C

in ATP+Mg2+ bound state, 2.12±0.41 °C in Mannose bound state and 3.07±0.41 °C in Mannose+ ATP+Mg2+ bound state. The apo and M7P +ATP + Mg2+ complexed models of

MtbHddA showed that enzyme adopts a classical GHMP sugar kinase fold with

conserved ATP+Mg2+ and M7P binding sites. The dynamics simulation analysis on

four MtbHddA models showed that ATP+Mg2+ and M7P binding enhanced the stability

of active site conformation of MtbHddA. Our study provides important insights

into MtbHddA structure and activity, which can be targeted for therapeutic

development against M. tuberculosis.

Copyright © 2020 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.ijbiomac.2020.12.191

PMID: 33412198

10. Med Res Rev. 2021 Jan 5. doi: 10.1002/med.21779. Online ahead of print.

QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular

agents.

Bahuguna A(1), Rawat S(1), Rawat DS(1).

Author information:

(1)Department of Chemistry, University of Delhi, Delhi, India.

Drug-resistance in mycobacterial infections is a major global health problem

that leads to high mortality and socioeconomic pressure in developing countries

around the world. From finding new targets to discovering novel chemical

scaffolds, there is an urgent need for the development of better approaches for

the cure of tuberculosis. Recently, energy metabolism in mycobacteria,

particularly the oxidative phosphorylation pathway of cellular respiration, has

emerged as a novel target pathway in drug discovery. New classes of

antibacterials which target oxidative phosphorylation pathway either by

interacting with a protein or any step in the pathway of oxidative

phosphorylation can combat dormant mycobacterial infections leading to

shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one

such recently discovered target of the newly approved antitubercular drug

bedaquiline. Cytochrome bcc is another new target of the antitubercular drug

candidate Q203, currently in phase II clinical trial. Research suggests that b

subunit of cytochrome bcc, QcrB, is the target of Q203. The review article

describes the structure, function, and importance of targeting QcrB throwing

light on all chemical classes of QcrB inhibitors discovered to date. An

understanding of the structure and function of validated targets and their

inhibitors would enable the development of new chemical entities.

© 2021 Wiley Periodicals LLC.

DOI: 10.1002/med.21779

PMID: 33400275

11. Cell Metab. 2021 Jan 4:S1550-4131(20)30671-9. doi: 10.1016/j.cmet.2020.12.016.

Online ahead of print.

Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection

from Tuberculosis.

Palma C(1), La Rocca C(2), Gigantino V(3), Aquino G(3), Piccaro G(4), Di

Silvestre D(5), Brambilla F(5), Rossi R(5), Bonacina F(6), Lepore MT(2), Audano

M(6), Mitro N(6), Botti G(7), Bruzzaniti S(8), Fusco C(9), Procaccini C(10), De

Rosa V(10), Galgani M(11), Alviggi C(12), Puca A(13), Grassi F(14),

Rezzonico-Jost T(14), Norata GD(15), Mauri P(16), Netea MG(17), de Candia P(18),

Matarese G(19).

Author information:

(1)Dipartimento Malattie Infettive, Istituto Superiore di Sanità, 00161 Roma,

Italy. Electronic address: carla.palma@iss.it.

(2)Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale

delle Ricerche (IEOS-CNR), 80131 Napoli, Italy.

(3)Pathology Unit, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS,

80131 Naples, Italy.

There is a strong relationship between metabolic state and susceptibility to

Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the

basis for an exaggerated immuno-inflammatory response, which concurs with MTB

pathogenesis. Herein, we show that controlled caloric restriction (CR), not

leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB

infection by reducing bacterial load, lung immunopathology, and generation of

foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a

metabolic shift toward glycolysis, and decreased both fatty acid oxidation and

mTOR activity associated with induction of autophagy in immune cells. An

integrated multi-omics approach revealed a specific CR-induced metabolomic,

transcriptomic, and proteomic signature leading to reduced lung damage and

protective remodeling of lung interstitial tightness able to limit MTB

spreading. Our data propose CR as a feasible immunometabolic manipulation to

control MTB infection, and this approach offers an unexpected strategy to boost

immunity against MTB.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2020.12.016

PMID: 33421383

12. NPJ Vaccines. 2021 Jan 4;6(1):4. doi: 10.1038/s41541-020-00262-8.

MTBVAC vaccination protects rhesus macaques against aerosol challenge with M.

tuberculosis and induces immune signatures analogous to those observed in

clinical studies.

White AD(1), Sibley L(2), Sarfas C(2), Morrison A(2), Gullick J(2), Clark S(2),

Gleeson F(3), McIntyre A(3), Arlehamn CL(4), Sette A(4), Salguero FJ(2), Rayner

E(2), Rodriguez E(5), Puentes E(5), Laddy D(6), Williams A(2), Dennis M(2),

Martin C(7), Sharpe S(2).

Author information:

(1)Public Health England, National Infection Service, Porton Down, Salisbury,

SP4 0JG, UK. Andrew.white@phe.gov.uk.

(2)Public Health England, National Infection Service, Porton Down, Salisbury,

SP4 0JG, UK.

(3)The Churchill Hospital, Headington, Oxford, UK.

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was

well tolerated and conferred a significant improvement in outcome following

aerosol exposure to M. tuberculosis compared to that provided by a single BCG

vaccination. Vaccination with MTBVAC resulted in a significant reduction in M.

tuberculosis infection-induced disease pathology measured using in vivo medical

imaging, in gross pathology lesion counts and pathology scores recorded at

necropsy, the frequency and severity of pulmonary granulomas and the frequency

of recovery of viable M. tuberculosis from extrapulmonary tissues following

challenge. The immune profiles induced following immunisation with MTBVAC

reflect those identified in human clinical trials of MTBVAC. Evaluation of

MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a

predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and

multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17

and cytokine-producing CD8 T-cell populations were detected together with

low-level, but significant, increases in CFP10-specific IFN-γ secreting cells.

In this report, we describe concordance between immune profiles measured in

clinical trials and a macaque pre-clinical study demonstrating significantly

improved outcome after M. tuberculosis challenge as evidence to support the

continued development of MTBVAC as an effective prophylactic vaccine for TB

vaccination campaigns.

DOI: 10.1038/s41541-020-00262-8

PMID: 33397991

13. NPJ Vaccines. 2021 Jan 4;6(1):3. doi: 10.1038/s41541-020-00263-7.

A non-human primate in vitro functional assay for the early evaluation of TB

vaccine candidates.

Tanner R(1), White AD(2), Boot C(3), Sombroek CC(3), O'Shea MK(4)(5), Wright

D(4), Hoogkamer E(4)(2), Bitencourt J(4)(6), Harris SA(4), Sarfas C(2),

Wittenberg R(4), Satti I(4), Fletcher HA(4)(7), Verreck FAW(3), Sharpe SA(2),

McShane H(4).

Author information:

(1)The Jenner Institute, University of Oxford, Oxford, UK.

rachel.tanner@ndm.ox.ac.uk.

(2)Public Health England, Salisbury, UK.

(3)TB Research Group, Department of Parasitology, Biomedical Primate Research

Centre, Rijswijk, Netherlands.

We present a non-human primate mycobacterial growth inhibition assay (MGIA)

using in vitro blood or cell co-culture with the aim of refining and expediting

early tuberculosis vaccine testing. We have taken steps to optimise the assay

using cryopreserved peripheral blood mononuclear cells, transfer it to end-user

institutes, and assess technical and biological validity. Increasing cell

concentration or mycobacterial input and co-culturing in static 48-well plates

compared with rotating tubes improved intra-assay repeatability and sensitivity.

Standardisation and harmonisation efforts resulted in high consistency

agreements, with repeatability and intermediate precision<10% coefficient of

variation (CV) and inter-site reproducibility<20% CV; although some systematic

differences were observed. As proof-of-concept, we demonstrated ability to

detect a BCG vaccine-induced improvement in growth inhibition in macaque

samples, and a correlation between MGIA outcome and measures of protection from

in vivo disease development following challenge with either intradermal BCG or

aerosol/endobronchial Mycobacterium tuberculosis (M.tb) at a group and

individual animal level.

DOI: 10.1038/s41541-020-00263-7

PMID: 33397986

14. J Med Chem. 2021 Jan 4. doi: 10.1021/acs.jmedchem.0c01727. Online ahead of

print.

Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and

Mode-of-Action Studies.

Soares de Melo C(1), Singh V(2)(3), Myrick A(2), Simelane SB(1), Taylor D(4),

Brunschwig C(4), Lawrence N(4), Schnappinger D(5), Engelhart CA(5), Kumar A(6),

Parish T(6), Su Q(7), Myers TG(7), Boshoff HIM(8), Barry CE 3rd(8), Sirgel

FA(9), van Helden PD(9), Buchanan KI(10), Bayliss T(10), Green SR(10), Ray

PC(10), Wyatt PG(10), Basarab GS(1)(4), Eyermann CJ(1), Chibale K(1)(3),

Ghorpade SR(1).

Author information:

(1)Drug Discovery and Development Centre (H3D), Department of Chemistry,

University of Cape Town, Rondebosch 7701, South Africa.

(2)Drug Discovery and Development Centre (H3D), University of Cape Town,

Rondebosch 7701, South Africa.

(3)South African Medical Research Council Drug Discovery and Development

Research Unit, Department of Chemistry and Institute of Infectious Disease and

Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.

Phenotypic screening of a Medicines for Malaria Venture compound library against

Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active

2-pyrazolylpyrimidinones. The biology triage of these actives using various tool

strains of Mtb suggested a novel mechanism of action. The compounds were

bactericidal against replicating Mtb and retained potency against clinical

isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance

to these compounds, there was no shift in the minimum inhibitory concentration

(MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible

resistance mechanism for the compounds but not necessarily as the target. RNA

transcriptional profiling and the checkerboard board 2D-MIC assay in the

presence of varying concentrations of ferrous salt indicated perturbation of the

Fe-homeostasis by the compounds. Structure-activity relationship studies

identified potent compounds with good physicochemical properties and in vitro

microsomal metabolic stability with moderate selectivity over cytotoxicity

against mammalian cell lines.

DOI: 10.1021/acs.jmedchem.0c01727

PMID: 33395287

15. Mol Biol Evol. 2021 Jan 4;38(1):290-306. doi: 10.1093/molbev/msaa179.

Multiple Merger Genealogies in Outbreaks of Mycobacterium tuberculosis.

Menardo F(1)(2), Gagneux S(1)(2), Freund F(3).

Author information:

(1)Department of Medical Parasitology and Infection Biology, Swiss Tropical and

Public Health Institute, Basel, Switzerland.

(2)University of Basel, Basel, Switzerland.

(3)Department of Plant Biodiversity and Breeding Informatics, Institute of Plant

Breeding, Seed Science and Population Genetics, University of Hohenheim,

Stuttgart, Germany.

The Kingman coalescent and its developments are often considered among the most

important advances in population genetics of the last decades. Demographic

inference based on coalescent theory has been used to reconstruct the population

dynamics and evolutionary history of several species, including Mycobacterium

tuberculosis (MTB), an important human pathogen causing tuberculosis. One key

assumption of the Kingman coalescent is that the number of descendants of

different individuals does not vary strongly, and violating this assumption

could lead to severe biases caused by model misspecification. Individual

lineages of MTB are expected to vary strongly in reproductive success because 1)

MTB is potentially under constant selection due to the pressure of the host

immune system and of antibiotic treatment, 2) MTB undergoes repeated population

bottlenecks when it transmits from one host to the next, and 3) some hosts show

much higher transmission rates compared with the average (superspreaders). Here,

we used an approximate Bayesian computation approach to test whether

multiple-merger coalescents (MMC), a class of models that allow for large

variation in reproductive success among lineages, are more appropriate models to

study MTB populations. We considered 11 publicly available whole-genome sequence

data sets sampled from local MTB populations and outbreaks and found that MMC

had a better fit compared with the Kingman coalescent for 10 of the 11 data

sets. These results indicate that the null model for analyzing MTB outbreaks

should be reassessed and that past findings based on the Kingman coalescent need

to be revisited.

© The Author(s) 2020. Published by Oxford University Press on behalf of the

Society for Molecular Biology and Evolution.

DOI: 10.1093/molbev/msaa179

PMID: 32667991

16. Clin Infect Dis. 2021 Jan 3:ciaa1934. doi: 10.1093/cid/ciaa1934. Online ahead of print.

Latent Tuberculosis Infection and Subclinical Coronary Atherosclerosis in Peru

and Uganda.

Huaman MA(1), De Cecco CN(2), Bittencourt MS(3), Ticona E(4)(5), Kityo C(6),

Isabel B(4), Nalukwago S(6), Nazzinda R(6), Ticona C(4), Azañero R(4), Zhang

B(7), Carey F(8), Thomas HR(8), Sterling TR(9), Carl FJ(1), Chris LT(10).

Author information:

(1)Department of Internal Medicine, Division of Infectious Diseases, University

of Cincinnati College of Medicine, Ohio, United States of America.

(2)Division of Cardiothoracic Imaging, Department of Radiology and Imaging

Sciences, Emory University School of Medicine, Atlanta, GA, United States of

America.

(3)Department of Cardiology, University Hospital, Sao Paulo, Brazil.

BACKGROUND: Tuberculosis has been linked to an increased risk of atherosclerotic

cardiovascular disease (ASCVD). We assessed whether latent tuberculosis

infection (LTBI) is associated with subclinical coronary atherosclerosis in two

TB-prevalent areas.

METHODS: We analyzed cross-sectional data from studies conducted in Lima, Peru,

and Kampala, Uganda. Individuals ≥40 years old were included. We excluded

persons with known history of ASCVD events or active TB. Participants underwent

QuantiFERON®-TB (QFT) testing to define LTBI, and computed tomography

angiography to examine coronary atherosclerosis. A Coronary Artery

Disease-Reporting Data System (CAD-RADS) score ≥3 defined obstructive CAD

(plaque causing ≥50% stenosis).

RESULTS: 113 persons with LTBI and 91 persons without LTBI were included. There

were no significant differences between LTBI and non-LTBI participants in terms

of age (median [interquartile range]; 56 [51-62] vs. 55 [49-64], p=0.829), male

sex (38% vs. 42%; p=0.519), or 10-year ASCVD risk scores (7.1 [3.2-11.7] vs. 6.1

[2.8-10.8]; p=0.533). CAD prevalence (any plaque) was similar between groups

(29% vs. 24%; p=0.421). Obstructive CAD was present in 9% of LTBI and 3% of

non-LTBI individuals; p=0.095. LTBI was associated with obstructive CAD after

adjusting for ASCVD risk score, HIV status, and study site (adjusted odds ratio,

4.96, 95% CI 1.05-23.44; p=0.043). Quantitative QFT TB antigen minus nil

interferon-gamma responses were associated with obstructive CAD (adjusted odds

ratio, 1.2, 95% CI 1.03-1.41; p=0.022).

CONCLUSIONS: LTBI was independently associated with an increased likelihood of

subclinical obstructive CAD. Our data indicates that LTBI is a non-traditional

correlate of ASCVD risk.

© The Author(s) 2021. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/cid/ciaa1934

PMID: 33388766

17. Lancet HIV. 2021 Jan;8(1):e8-e15. doi: 10.1016/S2352-3018(20)30299-X.

Isoniazid preventive therapy plus antiretroviral therapy for the prevention of

tuberculosis: a systematic review and meta-analysis of individual participant

data.

Ross JM(1), Badje A(2), Rangaka MX(3), Walker AS(3), Shapiro AE(4), Thomas

KK(5), Anglaret X(2), Eholie S(6), Gabillard D(2), Boulle A(7), Maartens G(8),

Wilkinson RJ(9), Ford N(10), Golub JE(11), Williams BG(12), Barnabas RV(4).

Author information:

(1)Department of Global Health, University of Washington, Seattle, WA, USA;

Department of Medicine, Division of Allergy and Infectious Diseases, University

of Washington, Seattle, WA, USA. Electronic address: jross3@uw.edu.

(2)University of Bordeaux, Bordeaux, France.

(3)MRC Clinical Trials Unit, University College London, London, UK.

BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people

with HIV, but previous studies have found no evidence of benefit in people with

HIV who had a negative tuberculin skin test, and a non-significant effect on

mortality. We aimed to estimate the effect of isoniazid preventive therapy given

with antiretroviral therapy (ART) for the prevention of tuberculosis and death

among people with HIV across population subgroups.

METHODS: We searched PubMed, Embase, the Cochrane database, and conference

abstracts from database inception to Jan 15, 2019, to identify potentially

eligible randomised trials. Eligible studies were trials that enrolled

HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to

either daily isoniazid preventive therapy plus ART or ART alone and followed up

longitudinally for outcomes of incident tuberculosis and mortality. We

approached all authors of included trials and requested individual participant

data: coprimary outcomes were relative risk of incident tuberculosis and

all-cause mortality. We did a single-stage meta-analysis of individual

participant data using stratified Cox-proportional hazards models. We did

prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune

sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ

release assays [IGRAs]). We also assessed the relative risk of liver injury in

an additional prespecified analysis. This study is registered with PROSPERO,

CRD42019121400.

FINDINGS: Of 838 records, we included three trials with data for 2611

participants and 8584·8 person-years of follow-up for the outcome of incident

tuberculosis, and a subset of 2362 participants with 8631·6 person-years of

follow-up for the coprimary outcome of all-cause mortality. Risk for

tuberculosis was lower in participants given isoniazid preventive therapy and

ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95,

p=0·02). Risk of all-cause mortality was lower in participants given isoniazid

preventive therapy and ART than participants given ART alone, but this

difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants

with baseline CD4 counts of less than 500 cells per μL had increased risk of

tuberculosis, but there was no significant difference in the benefit of

isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of

tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine

aminotransferase, but data were insufficient to calculate an HR.

INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis

across demographic and HIV-specific and tuberculosis-specific subgroups, which

supports efforts to further increase use of isoniazid preventive therapy with

ART broadly among people living with HIV.

FUNDING: National Institutes of Health and National Institute of Allergy and

Infectious Diseases.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S2352-3018(20)30299-X

PMID: 33387480

18. Eur Respir J. 2021 Jan 5;57(1):2003890. doi: 10.1183/13993003.03890-2020. Print

2021 Jan.

Impact of the COVID-19 pandemic on tuberculosis laboratory services in Europe.

Nikolayevskyy V(1)(2), Holicka Y(1), van Soolingen D(3), van der Werf MJ(4),

Ködmön C(4), Surkova E(5), Hillemann D(6), Groenheit R(7); ERLTB-Net-2 study

participants, Cirillo D(8).

Author information:

(1)Public Health England, London, UK.

(2)Imperial College London, London, UK.

(3)National Institute for Public Health and the Environment (RIVM), Bilthoven,

The Netherlands.

The coronavirus disease 2019 (COVID-19) pandemic and associated response have

undoubtedly had a dramatic multidimensional impact on healthcare services

globally, severely disrupting care for many chronic diseases [1, 2]. Direct

impact on communicable diseases, such as tuberculosis (TB), especially in

developing countries disproportionally affected by TB, is not yet fully

understood but is very likely to put national TB programmes under immense

pressure and lead to an increase in TB deaths of 8–20% in the near future [3–5].

This predicted increase is largely caused by delays in diagnosis and treatment

of new TB cases due to non-pharmaceutical interventions implemented nationally

and globally, in order to contain virus transmission [3, 6–8]. Combined COVID-19

and TB infection also poses a challenge from various perspectives [9]. It is

anticipated that the number of co-infected patients increases as the pandemic

progresses.

DOI: 10.1183/13993003.03890-2020

PMCID: PMC7670866

PMID: 33184119

19. Epidemiology. 2021 Jan;32(1):70-78. doi: 10.1097/EDE.0000000000001271.

Time Since Infection and Risks of Future Disease for Individuals with

Mycobacterium tuberculosis Infection in the United States.

Menzies NA(1), Swartwood N(1), Testa C(1), Malyuta Y(1), Hill AN(2), Marks

SM(2), Cohen T(3), Salomon JA(4).

Author information:

(1)From the Harvard T.H. Chan School of Public Health, Boston, MA.

(2)Division of Tuberculosis Elimination, Centers for Disease Control and

Prevention, Atlanta, GA.

(3)Department of Epidemiology of Microbial Diseases, Yale School of Public

Health, New Haven, CT.

(4)Department of Medicine, Stanford University, Palo Alto, CA.

BACKGROUND: Risk of tuberculosis (TB) declines over time since Mycobacterium

tuberculosis infection, but progression to clinical disease is still possible

decades later. In the United States, most TB cases result from the progression

of latent TB infection acquired over 2 years ago.

METHODS: We synthesized evidence on TB natural history and incidence trends

using a transmission-dynamic model. For the 2020 US population, we estimated

average time since infection and annual, cumulative, and remaining lifetime

risks of progression to TB, by nativity and age.

RESULTS: For a newly infected adult with no other risk factors for progression

to TB, estimated rates of progression declined from 38 (95% uncertainty

interval: 33, 46) to 0.38 (0.32, 0.45) per 1000 person-years between the first

and 25th year since infection. Cumulative risk over 25 years from new infection

was 7.9% (7.0, 8.9). In 2020, an estimated average age of individuals with

prevalent infection was 62 (61, 63) for the US-born population, 55 (54, 55) for

non-US-born, and 57 (56, 58) overall. Average risks of developing TB over the

remaining lifetime were 1.2% (1.0, 1.4) for US-born, 2.2% (1.8, 2.6) for

non-US-born, and 1.9% (1.6, 2.2) for the general population. Risk estimates were

higher for younger age groups.

CONCLUSIONS: Our analysis suggests that, although newly infected individuals

face appreciable lifetime TB risks, most US individuals with latent TB infection

were infected long ago, and face low future risks of developing TB. Better

approaches are needed for identifying recently infected individuals and those

with elevated progression risks.

DOI: 10.1097/EDE.0000000000001271

PMCID: PMC7707158

PMID: 33009253

20. Eur Respir J. 2021 Jan 5;57(1):2002272. doi: 10.1183/13993003.02272-2020. Print

2021 Jan.

Use of a whole genome sequencing-based approach for Mycobacterium tuberculosis

surveillance in Europe in 2017-2019: an ECDC pilot study.

Tagliani E(1), Anthony R(2)(3), Kohl TA(4)(5)(3), de Neeling A(2), Nikolayevskyy

V(6)(7), Ködmön C(8), Maurer FP(9)(10), Niemann S(4)(5), van Soolingen D(2), van

der Werf MJ(8), Cirillo DM; ECDC molecular surveillance project participants.

Author information:

(1)Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation

and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.

(2)Tuberculosis Reference Laboratory, Infectious Diseases Research, Diagnostics

and Laboratory Surveillance (IDS), National Institute for Public Health and the

Environment (RIVM), Bilthoven, The Netherlands.

(3)Both authors contributed equally.

Whole genome sequencing (WGS) can be used for molecular typing and

characterisation of Mycobacterium tuberculosis complex (MTBC) strains. We

evaluated the systematic use of a WGS-based approach for MTBC surveillance

involving all European Union/European Economic Area (EU/EEA) countries and

highlight the challenges and lessons learnt to be considered for the future

development of a WGS-based surveillance system.WGS and epidemiological data of

patients with rifampicin-resistant (RR) and multidrug-resistant (MDR)

tuberculosis (TB) were collected from EU/EEA countries between January 2017 and

December 2019. WGS-based genetic relatedness analysis was performed using a

standardised approach including both core genome multilocus sequence typing

(cgMLST) and single nucleotide polymorphism (SNP)-based calculation of distances

on all WGS data that fulfilled minimum quality criteria to ensure data

comparability.A total of 2218 RR/MDR-MTBC isolates were collected from 25

countries. Among these, 56 cross-border clusters with increased likelihood of

recent transmission (≤5 SNPs distance) comprising 316 RR/MDR-MTBC isolates were

identified. The cross-border clusters included between two and 30 resistant

isolates from two to six countries, demonstrating different RR/MDR-TB

transmission patterns in Western and Eastern EU countries.This pilot study shows

that a WGS-based surveillance system is not only feasible but can efficiently

elucidate the dynamics of in-country and cross-border RR/MDR-TB transmission

across EU/EEA countries. Lessons learnt from this study highlight that the

establishment of an EU/EEA centralised WGS-based surveillance system for TB will

require strengthening of national integrated systems performing prospective WGS

surveillance and the development of clear procedures to facilitate international

collaboration for the investigation of cross-border clusters.

Copyright ©ERS 2021.

DOI: 10.1183/13993003.02272-2020

PMID: 32732329

21. Am J Respir Crit Care Med. 2021 Jan 1;203(1):111-119. doi:

10.1164/rccm.202001-0135OC.

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A

Prospective Multicountry Study.

Franke MF(1)(2), Khan P(3), Hewison C(4), Khan U(3), Huerga H(5), Seung

KJ(2)(6),…

Author information:

(1)Department of Global Health and Social Medicine, Harvard Medical School,

Boston, Massachusetts.

(2)Partners In Health, Boston, Massachusetts.

(3)Interactive Research and Development, Karachi, Pakistan.

Comment in

   Am J Respir Crit Care Med. 2021 Jan 1;203(1):11-13.

Rationale: Bedaquiline and delamanid offer the possibility of more effective and

less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this

treatment, however, some patients remain at high risk for an unfavorable

treatment outcome. The endTB Observational Study is the largest multicountry

cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care

with delamanid- and/or bedaquiline-containing regimens according to World Health

Organization guidance.Objectives: We report the frequency of sputum culture

conversion within 6 months of treatment initiation and the risk factors for

nonconversion.Methods: We included patients with a positive baseline culture who

initiated a first endTB regimen before April 2018. Two consecutive negative

cultures collected 15 days or more apart constituted culture conversion. We used

generalized mixed models to derive marginal predictions for the probability of

culture conversion in key subgroups.Measurements and Main Results: A total of

1,109 patients initiated a multidrug treatment containing bedaquiline (63%),

delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture

conversion within 6 months. In adjusted analyses, patients with HIV had a lower

probability of conversion (0.73; 95% confidence interval [CI], 0.62-0.84) than

patients without HIV (0.84; 95% CI, 0.79-0.90; P=0.03). Patients with both

cavitary disease and highly positive sputum smear had a lower probability of

conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89;

95% CI, 0.84-0.95; P=0.0004). Hepatitis C infection, diabetes mellitus or

glucose intolerance, and baseline resistance were not associated with

conversion.Conclusions: Frequent sputum conversion in patients with

rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or

delamanid underscores the need for urgent expanded access to these drugs. There

is a need to optimize treatment for patients with HIV and extensive disease.

DOI: 10.1164/rccm.202001-0135OC

PMID: 32706644

22. Nature. 2021 Jan;589(7840):143-147. doi: 10.1038/s41586-020-3004-3. Epub 2020

Dec 9.

Structure of mycobacterial ATP synthase bound to the tuberculosis drug

bedaquiline.

Guo H(1)(2), Courbon GM(1)(2), Bueler SA(1), Mai J(3), Liu J(3), Rubinstein

JL(4)(5)(6).

Author information:

(1)Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario,

Canada.

(2)Department of Medical Biophysics, The University of Toronto, Toronto,

Ontario, Canada.

(3)Department of Molecular Genetics, The University of Toronto, Toronto,

Ontario, Canada.

Tuberculosis-the world's leading cause of death by infectious disease-is

increasingly resistant to current first-line antibiotics1. The bacterium

Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy

conditions, allowing infections to remain dormant and decreasing their

susceptibility to many antibiotics2. Bedaquiline was developed in 2005 from a

lead compound identified in a phenotypic screen against Mycobacterium

smegmatis3. This drug can sterilize even latent M. tuberculosis? infections4 and

has become a cornerstone of treatment for multidrug-resistant and extensively

drug-resistant tuberculosis1,5,6. Bedaquiline targets the mycobacterial ATP

synthase3, which is an essential enzyme in the obligate aerobic Mycobacterium

genus3,7, but how it binds the intact enzyme is unknown. Here we determined

cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in

complex with bedaquiline. The drug-free structure suggests that hook-like

extensions from the α-subunits prevent the enzyme from running in reverse,

inhibiting ATP hydrolysis and preserving energy in hypoxic conditions.

Bedaquiline binding induces large conformational changes in the ATP synthase,

creating tight binding pockets at the interface of subunits a and c that explain

the potency of this drug as an antibiotic for tuberculosis.

DOI: 10.1038/s41586-020-3004-3

PMID: 33299175

23. Nat Microbiol. 2021 Jan;6(1):44-50. doi: 10.1038/s41564-020-00810-x. Epub 2020

Nov 16.

Transcriptional regulator-induced phenotype screen reveals drug potentiators in

Mycobacterium tuberculosis.

Ma S(1)(2), Morrison R(1), Hobbs SJ(2), Soni V(3)(4), Farrow-Johnson J(1)(2),

Frando A(2)(5), Fleck N(2)(5), Grundner C(2)(5), Rhee KY(3)(4), Rustad TR(2),

Sherman DR(6)(7).

Author information:

(1)Department of Microbiology, University of Washington, Seattle, WA, USA.

(2)Interdisciplinary Program of Pathobiology, Department of Global Health,

University of Washington, Seattle, WA, USA.

(3)Division of Infectious Diseases, Department of Medicine, Weill Cornell

Medical College, New York, NY, USA.

Transposon-based strategies provide a powerful and unbiased way to study the

bacterial stress response1-8, but these approaches cannot fully capture the

complexities of network-based behaviour. Here, we present a network-based

genetic screening approach: the transcriptional regulator-induced phenotype

(TRIP) screen, which we used to identify previously uncharacterized network

adaptations of Mycobacterium tuberculosis to the first-line anti-tuberculosis

drug isoniazid (INH). We found regulators that alter INH susceptibility when

induced, several of which could not be identified by standard gene disruption

approaches. We then focused on a specific regulator, mce3R, which potentiated

INH activity when induced. We compared mce3R-regulated genes with baseline INH

transcriptional responses and implicated the gene ctpD (Rv1469) as a putative

INH effector. Evaluating a ctpD disruption mutant demonstrated a previously

unknown role for this gene in INH susceptibility. Integrating TRIP screening

with network information can uncover sophisticated molecular response programs.

DOI: 10.1038/s41564-020-00810-x

PMID: 33199862

24. Eur J Med Chem. 2021 Jan 1;209:112898. doi: 10.1016/j.ejmech.2020.112898. Epub

2020 Oct 10.

Design, synthesis, and evaluation of substituted 2-acylamide-1,3-benzo[d]zole

analogues as agents against MDR- and XDR-MTB.

Li D(1), Liu C(1), Jiang X(1), Lin Y(1), Zhang J(1), Li Y(1), You X(1), Jiang

W(1), Chen M(2), Xu Y(3), Si S(4).

Author information:

(1)Beijing Key Laboratory of Antimicrobial Agents, And National Center for New

Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy

of Medical Sciences & Peking Union Medical College, Tiantanxili No 1, Beijing,

100050, PR China.

(2)Beijing Key Laboratory of Antimicrobial Agents, And National Center for New

Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy

of Medical Sciences & Peking Union Medical College, Tiantanxili No 1, Beijing,

100050, PR China. Electronic address: mingsunlight@sina.com.

(3)Beijing Key Laboratory of Antimicrobial Agents, And National Center for New

Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy

of Medical Sciences & Peking Union Medical College, Tiantanxili No 1, Beijing,

100050, PR China. Electronic address: xuyanniwendeng@hotmail.com.

N-(5-Chlorobenzo[d]oxazol-2-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamideox-amide

has been identified as a potent inhibitor of Mtb H37Rv, with a minimum

inhibitory concentration (MIC) of 0.42 μM. In this study, a series of

substituted 2-acylamide-1,3-zole analogues were designed and synthesized, and

their anti-Mtb activities were analyzed. In total, 17 compounds were found to be

potent anti-Mtb agents, especially against the MDR- and XDR-MTB strains, with

MIC values < 10 μM. These analogues can inhibit both drug-sensitive and

drug-resistant Mtb. Four representative compounds were selected for further

profiling, and the results indicate that compound 18 is acceptably safe and has

favorable pharmacokinetic (PK) properties. In addition, this compound displays

potent activity against Gram-positive bacteria, with MIC values in the range of

1.48-11.86 μM. The data obtained herein suggest that promising anti-Mtb

candidates may be developed via structural modification, and that further

research is needed to explore other compounds.

Copyright © 2020 Elsevier Masson SAS. All rights reserved.

DOI: 10.1016/j.ejmech.2020.112898

PMID: 33069433

25. Eur J Med Chem. 2021 Jan 1;209:112859. doi: 10.1016/j.ejmech.2020.112859. Epub

2020 Sep 23.

Anti-tubercular profile of new selenium-menadione conjugates against

Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant

clinical isolates.

Ribeiro RCB(1), de Marins DB(1), Di Leo I(1), da Silva Gomes L(1), de Moraes

MG(1), Abbadi BL(2), Villela AD(2), da Silva WF(3), da Silva LCRP(3), Machado

P(2), Bizarro CV(2), Basso LA(2), Cristina de Moraes M(1), Ferreira VF(4), da

Silva FC(1), Nascimento V(5).

Author information:

(1)Universidade Federal Fluminense, Departamento de Química Orgânica, Instituto

de Química, Campus Do Valonguinho, CEP 24020-150, Niterói, RJ, Brazil.

(2)Instituto Nacional de Ciência e Tecnologia Em Tuberculose (INCT-TB), Centro

de Pesquisas Em Biologia Molecular e Funcional, Pontifícia Universidade Católica

Do Rio Grande Do Sul, PUCRS, Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900,

Porto Alegre, RS, Brazil.

(3)Universidade Federal Do Rio de Janeiro, Faculdade de Farmácia, CEP 21941-902,

Rio de Janeiro, RJ, Brazil.

Tuberculosis (TB) is one of the most fatal diseases and is responsible for the

infection of millions of people around the world. Most recently, scientific

frontiers have been engaged to develop new drugs that can overcome

drug-resistant TB. Following this direction, using a designed scaffold based on

the combination of two separate pharmacophoric groups, a series of

menadione-derived selenoesters was developed with good yields. All products were

evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv

and attractive results were observed, especially for the compounds 8a, 8c and 8f

(MICs 2.1, 8.0 and 8.1 μM, respectively). In addition, 8a, 8c and 8f

demonstrated potent in vitro activity against multidrug-resistant clinical

isolates (CDCT-16 and CDCT-27) with promising MIC values ranging from 0.8 to

3.1 μM. Importantly, compounds 8a and 8c were found to be non-toxic against the

Vero cell line. The SI value of 8a (>23.8) was found to be comparable to that of

isoniazid (>22.7), which suggests the possibility of carrying out advanced

studies on this derivative. Therefore, these menadione-derived selenoesters

obtained as hybrid compounds represent promising new anti-tubercular agents to

overcome TB multidrug resistance.

Copyright © 2020 Elsevier Masson SAS. All rights reserved.

DOI: 10.1016/j.ejmech.2020.112859

PMCID: PMC7510590

PMID: 33010635

26. Mucosal Immunol. 2021 Jan;14(1):253-266. doi: 10.1038/s41385-020-00342-x. Epub

2020 Aug 29.

Heme oxygenase-1 inhibition promotes IFNγ- and NOS2-mediated control of

Mycobacterium tuberculosis infection.

Costa DL(1), Amaral EP(2), Namasivayam S(2), Mittereder LR(2), Fisher L(2),

Bonfim CC(2), Sardinha-Silva A(3), Thompson RW(4), Hieny SE(2), Andrade

BB(2)(5)(6)(7)(8)(9)(10)(11), Sher A(2).

Author information:

(1)Immunobiology Section, Laboratory of Parasitic Diseases, National Institute

of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD,

USA. dlcosta@usp.br.

(2)Immunobiology Section, Laboratory of Parasitic Diseases, National Institute

of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD,

USA.

(3)Molecular Parasitology Section, Laboratory of Parasitic Diseases, National

Institute of Allergy and Infectious Diseases, National Institutes of Health,

Bethesda, MD, USA.

Mycobacterium tuberculosis (Mtb) infection induces pulmonary expression of the

heme-degrading enzyme heme oxygenase-1 (HO-1). We have previously shown that

pharmacological inhibition of HO-1 activity in experimental tuberculosis results

in decreased bacterial loads and unexpectedly that this outcome depends on the

presence of T lymphocytes. Here, we extend these findings by demonstrating that

IFNγ production by T lymphocytes and NOS2 expression underlie this T-cell

requirement and that HO-1 inhibition potentiates IFNγ-induced NOS2-dependent

control of Mtb by macrophages in vitro. Among the products of heme degradation

by HO-1 (biliverdin, carbon monoxide, and iron), only iron supplementation

reverted the HO-1 inhibition-induced enhancement of bacterial control and this

reversal was associated with decreased NOS2 expression and NO production. In

addition, we found that HO-1 inhibition results in decreased labile iron levels

in Mtb-infected macrophages in vitro and diminished iron accumulation in

Mtb-infected lungs in vivo. Together these results suggest that the T-lymphocyte

dependence of the therapeutic outcome of HO-1 inhibition on Mtb infection

reflects the role of the enzyme in generating iron that suppresses

T-cell-mediated IFNγ/NOS2-dependent bacterial control. In broader terms, our

findings highlight the importance of the crosstalk between iron metabolism and

adaptive immunity in determining the outcome of infection.

DOI: 10.1038/s41385-020-00342-x

PMCID: PMC7796944

PMID: 32862202

27. Mucosal Immunol. 2021 Jan;14(1):199-208. doi: 10.1038/s41385-020-0332-4. Epub

2020 Aug 18.

MAIT cell-directed therapy of Mycobacterium tuberculosis infection.

Sakai S(1), Kauffman KD(1), Oh S(2), Nelson CE(1), Barry CE 3rd(2), Barber

DL(3).

Author information:

(1)T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National

Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.

(2)Tuberculosis Research Section, Laboratory of Clinical Immunology and

Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda,

MD, USA.

(3)T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National

Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.

barberd@niaid.nih.gov.

Mucosal-associated invariant T (MAIT) cells are potential targets of vaccination

and host-directed therapeutics for tuberculosis, but the role of MAIT cells

during Mycobacterium tuberculosis (Mtb) infection in vivo is not well

understood. Here we find that following Mtb infection MAIT cells mount minimal

responses, and MAIT cell-deficient MR1-/- mice display normal survival.

Preinfection expansion of MAIT cells through 5-OP-RU vaccination fails to

protect against subsequent Mtb challenge. In fact, 5-OP-RU vaccination delays

Mtb-specific CD4 T cell priming in lung-draining lymph nodes, and conversely MR1

deficiency or blockade accelerates T cell priming. The MAIT cell-mediated delay

in T cell priming is partly dependent on TGF-β. Surprisingly, 5-OP-RU treatment

during chronic infection drives MAIT cell expansion and an IL-17A-dependent

reduction in bacterial loads. Thus, during early infection MAIT cells directly

contribute to the notoriously slow priming of CD4 T cells, but later during

infection MAIT cell stimulation may be an effective host-directed therapy for

tuberculosis.

DOI: 10.1038/s41385-020-0332-4

PMCID: PMC7790750

PMID: 32811991

28. Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:495-516. doi:

10.1146/annurev-pharmtox-030920-011143. Epub 2020 Aug 17.

Development of New Tuberculosis Drugs: Translation to Regimen Composition for

Drug-Sensitive and Multidrug-Resistant Tuberculosis.

Ernest JP(1), Strydom N(1), Wang Q(1), Zhang N(1), Nuermberger E(2), Dartois

V(3), Savic RM(1).

Author information:

(1)Department of Bioengineering and Therapeutic Sciences, University of

California, San Francisco, California 94158, USA; email: rada.savic@ucsf.edu.

(2)Center for Tuberculosis Research, Johns Hopkins University School of

Medicine, Baltimore, Maryland 21231, USA.

(3)Center for Discovery and Innovation, Hackensack Meridian School of Medicine

at Seton Hall University, Nutley, New Jersey 07110, USA.

Tuberculosis (TB) kills more people than any other infectious disease.

Challenges for developing better treatments include the complex pathology due to

within-host immune dynamics, interpatient variability in disease severity and

drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of

resistance. Model-informed drug development using quantitative and translational

pharmacology has become increasingly recognized as a method capable of drug

prioritization and regimen optimization to efficiently progress compounds

through TB drug development phases. In this review, we examine translational

models and tools, including plasma PK scaling, site-of-disease lesion PK,

host-immune and bacteria interplay, combination PK-PD models of multidrug

regimens, resistance formation, and integration of data across nonclinical and

clinical phases.We propose a workflow that integrates these tools with

computational platforms to identify drug combinations that have the potential to

accelerate sterilization, reduce relapse rates, and limit the emergence of

resistance.

DOI: 10.1146/annurev-pharmtox-030920-011143

PMCID: PMC7790895

PMID: 32806997

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