2021年
No.1
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/100 000 population) to intermediate (10-100/100 000) or high
(>100/100 000) 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 1 154 673 travellers observed
between 1994 and 2013, comprising 443 health care workers (HCW), 1 068 636
military personnel and 85 594 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 100 000 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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