Medical Abstracts

Keyword: tuberculosis

1. N Engl J Med. 2019 Dec 19;381(25):2429-2439. doi: 10.1056/NEJMoa1909953. Epub

2019 Oct 29.

Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

Tait DR(1), Hatherill M(1), Van Der Meeren O(1), Ginsberg AM(1), Van Brakel E(1),

Salaun B(1), Scriba TJ(1), Akite EJ(1), Ayles HM(1), Bollaerts A(1), Demoitié

MA(1), Diacon A(1), Evans TG(1), Gillard P(1), Hellström E(1), Innes JC(1),

Lempicki M(1), Malahleha M(1), Martinson N(1), Mesia Vela D(1), Muyoyeta M(1),

Nduba V(1), Pascal TG(1), Tameris M(1), Thienemann F(1), Wilkinson RJ(1), Roman

F(1).

Author information:

(1)From the International AIDS Vaccine Initiative (IAVI) (D.R.T.), the South

African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and

Molecular Medicine and Division of Immunology, Department of Pathology (M.H.,

T. J.S., M.T.), ...

U. Comment in

Nature. 2020 Jan;577(7789):145.

BACKGROUND: Results of an earlier analysis of a trial of the M72/AS01E candidate

vaccine against Mycobacterium tuberculosis showed that in infected adults, the

vaccine provided 54.0% protection against active pulmonary tuberculosis disease,

without evident safety concerns. We now report the results of the 3-year final

analysis of efficacy, safety, and immunogenicity.

METHODS: From August 2014 through November 2015, we enrolled adults 18 to 50

years of age with M. tuberculosis infection (defined by positive results on

interferon-γ release assay) without evidence of active tuberculosis disease at

centers in Kenya, South Africa, and Zambia. Participants were randomly assigned

in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered

1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to

prevent active pulmonary tuberculosis disease according to the first case

definition (bacteriologically confirmed pulmonary tuberculosis not associated

with human immunodeficiency virus infection). Participants were followed for 3

years after the second dose. Participants with clinical suspicion of tuberculosis

provided sputum samples for polymerase-chain-reaction assay, mycobacterial

culture, or both. Humoral and cell-mediated immune responses were evaluated until

month 36 in a subgroup of 300 participants. Safety was assessed in all

participants who received at least one dose of M72/AS01E or placebo.

RESULTS: A total of 3575 participants underwent randomization, of whom 3573

received at least one dose of M72/AS01E or placebo, and 3330 received both

planned doses. Among the 3289 participants in the according-to-protocol efficacy

cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26

of the 1663 participants in the placebo group, had cases of tuberculosis that met

the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years).

The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to

71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the

concentrations of M72-specific antibodies and the frequencies of M72-specific

CD4+ T cells increased after the first dose and were sustained throughout the

follow-up period. Serious adverse events, potential immune-mediated diseases, and

deaths occurred with similar frequencies in the two groups.

CONCLUSIONS: Among adults infected with M. tuberculosis, vaccination with

M72/AS01E elicited an immune response and provided protection against progression

to pulmonary tuberculosis disease for at least 3 years. (Funded by

GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).

Copyright © 2019 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1909953

PMID: 31661198 [Indexed for MEDLINE]

2. N Engl J Med. 2019 Oct 3;381(14):1347-1357. doi: 10.1056/NEJMoa1902129.

Community-wide Screening for Tuberculosis in a High-Prevalence Setting.

Marks GB(1), Nguyen NV(1), Nguyen PTB(1), Nguyen TA(1), Nguyen HB(1), Tran KH(1),

Nguyen SV(1), Luu KB(1), Tran DTT(1), Vo QTN(1), Le OTT(1), Nguyen YH(1), Do

VQ(1), Mason PH(1), Nguyen VT(1), Ho J(1), Sintchenko V(1), Nguyen LN(1), Britton

WJ(1), Fox GJ(1).

Author information:

(1)From the Woolcock Institute of Medical Research (G.B.M., P.T.B.N., T.-A.N.,

K.B.L., D.T.T.T., Q.T.N.V., O.T.T.L., Y.H.N., P.H.M., J.H., G.J.F.), the National

Lung Hospital (N.V.N., H.B.N.), the National Institute of Hygiene and

Epidemiology (V.-A.T.N..),...

BACKGROUND: The World Health Organization has set ambitious targets for the

global elimination of tuberculosis. However, these targets will not be achieved

at the current rate of progress.

METHODS: We performed a cluster-randomized, controlled trial in Ca Mau Province,

Vietnam, to evaluate the effectiveness of active community-wide screening, as

compared with standard passive case detection alone, for reducing the prevalence

of tuberculosis. Persons 15 years of age or older who resided in 60 intervention

clusters (subcommunes) were screened for pulmonary tuberculosis, regardless of

symptoms, annually for 3 years, beginning in 2014, by means of rapid nucleic acid

amplification testing of spontaneously expectorated sputum samples. Active

screening was not performed in the 60 control clusters in the first 3 years. The

primary outcome, measured in the fourth year, was the prevalence of

microbiologically confirmed pulmonary tuberculosis among persons 15 years of age

or older. The secondary outcome was the prevalence of tuberculosis infection, as

assessed by an interferon gamma release assay in the fourth year, among children

born in 2012.

RESULTS: In the fourth-year prevalence survey, we tested 42,150 participants in

the intervention group and 41,680 participants in the control group. A total of

53 participants in the intervention group (126 per 100,000 population) and 94

participants in the control group (226 per 100,000) had pulmonary tuberculosis,

as confirmed by a positive nucleic acid amplification test for Mycobacterium

tuberculosis (prevalence ratio, 0.56; 95% confidence interval [CI], 0.40 to 0.78;

P<0.001). The prevalence of tuberculosis infection in children born in 2012 was

3.3% in the intervention group and 2.6% in the control group (prevalence ratio,

1.29; 95% CI, 0.70 to 2.36; P = 0.42).

CONCLUSIONS: Three years of community-wide screening in persons 15 years of age

or older who resided in Ca Mau Province, Vietnam, resulted in a lower prevalence

of pulmonary tuberculosis in the fourth year than standard passive case detection

alone. (Funded by the Australian National Health and Medical Research Council;

ACT3 Australian New Zealand Clinical Trials Registry number,

ACTRN12614000372684.).

Copyright © 2019 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1902129

PMID: 31577876 [Indexed for MEDLINE]

3. Nat Commun. 2019 Oct 31;10(1):4970. doi: 10.1038/s41467-019-12956-2.

Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on

tuberculosis drug development.

Beites T(1), O'Brien K(1), Tiwari D(1), Engelhart CA(1), Walters S(1)(2), Andrews

J(3), Yang HJ(3), Sutphen ML(3), Weiner DM(3), Dayao EK(3), Zimmerman M(4),

Prideaux B(4), Desai PV(5), Masquelin T(5), Via LE(3)(6), Dartois V(4), Boshoff

HI(3), Barry CE 3rd(3)(6), Ehrt S(1), Schnappinger D(7).

Author information:

(1)Department of Microbiology and Immunology, Weill Cornell Medical College, New

York, NY, 10065, USA.

...

The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by

its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase

(NDH-2) are respiratory chain components predicted to be essential, and

are currently targeted for drug development. Here we demonstrate that an Mtb

cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially

attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a

cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces

lesion-associated inflammation, but most lesions become cavitary. Deletion of

both NDH-2 encoding genes (Δndh-2 mutant) reveals that the essentiality of NDH-2

as shown in standard growth media is due to the presence of fatty acids. The

Δndh-2 mutant is only mildly attenuated in mice and not differently susceptible

to clofazimine, a drug in clinical use proposed to engage NDH-2. These results

demonstrate the intrinsic plasticity of Mtb's respiratory chain, and highlight

the challenges associated with targeting the pathogen's respiratory enzymes for

tuberculosis drug development.

DOI: 10.1038/s41467-019-12956-2

PMCID: PMC6823465

PMID: 31672993

4. Clin Microbiol Rev. 2019 Oct 30;33(1). pii: e00100-19. doi: 10.1128/CMR.00100-19.

Print 2019 Dec 18.

Tuberculosis Vaccine Development: Progress in Clinical Evaluation.

Sable SB(1), Posey JE(2), Scriba TJ(3)(4)(5).

Author information:

(1)Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral

Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention,

Atlanta, Georgia, USA SSable@cdc.gov.

...

SUMMARYTuberculosis (TB) is the leading killer among all infectious diseases

worldwide despite extensive use of the Mycobacterium bovis bacille

Calmette-Guérin (BCG) vaccine. A safer and more effective vaccine than BCG is

urgently required. More than a dozen TB vaccine candidates are under active

evaluation in clinical trials aimed to prevent infection, disease, and

recurrence. After decades of extensive research, renewed promise of an effective

vaccine against this ancient airborne disease has recently emerged. In two

innovative phase 2b vaccine clinical trials, one for the prevention of

Mycobacterium tuberculosis infection in healthy adolescents and another for the

prevention of TB disease in M. tuberculosis-infected adults, efficacy signals

were observed. These breakthroughs, based on the greatly expanded knowledge of

the M. tuberculosis infection spectrum, immunology of TB, and vaccine platforms,

have reinvigorated the TB vaccine field. Here, we review our current

understanding of natural immunity to TB, limitations in BCG immunity that are

guiding vaccinologists to design novel TB vaccine candidates and concepts, and

the desired attributes of a modern TB vaccine. We provide an overview of the

progress of TB vaccine candidates in clinical evaluation, perspectives on the

challenges faced by current vaccine concepts, and potential avenues to build on

recent successes and accelerate the TB vaccine research-and-development

trajectory.

This is a work of the U.S. Government and is not subject to copyright protection

in the United States. Foreign copyrights may apply.

DOI: 10.1128/CMR.00100-19

PMCID: PMC6822991 [Available on 2020-10-30]

PMID: 31666281

5. Am J Respir Crit Care Med. 2019 Oct 28. doi: 10.1164/rccm.201908-1506PP. [Epub

ahead of print]

Reconsidering the Optimal Immune Response to Mycobacterium tuberculosis.

Tezera LB(1), Mansour S(2), Elkington P(3).

Author information:

(1)6NIHR Respiratory Biomedical Research Unit, University of Southampton,

Southampton, United Kingdom of Great Britain and Northern Ireland.

(2)University of Southampton, Academic Unit of Clinical & Experimental Sciences,

Faculty of Medicine, Southampton, United Kingdom of Great Britain and Northern

Ireland.

(3)University of Southampton, Southampton, United Kingdom of Great Britain and

Northern Ireland; p.elkington@soton.ac.uk.

Tuberculosis is unfortunately once again killing more people than any other

infection. Despite global biomedical and public health efforts, standard

interventions to control the pandemic have not advanced in most resource-poor

settings, in contrast to other global diseases such as malaria and HIV infection.

The authors propose that reconsidering concepts of the optimal host immune

response to Mycobacterium tuberculosis is required to develop a paradigm that

will inform novel interventions. The development of active tuberculosis

associated with cancer treatment by immune checkpoint inhibition highlights that

merely driving a stronger immune response may not improve control of the

pathogen. Here, we present different models of the host-pathogen interaction that

are consistent with the complexity of human infection. We consider both the

protective and harmful components of the immune response in tuberculosis and

develop a multiparameter framework that predicts disease risk. This novel

conceptual model is important to inform emerging interventions to improve

outcomes in tuberculosis by defining the ideal host response to target.

DOI: 10.1164/rccm.201908-1506PP

PMID: 31657633

6. Sci Transl Med. 2019 Oct 23;11(515). pii: eaaw8287. doi:

10.1126/scitranslmed.aaw8287.

A rapid triage test for active pulmonary tuberculosis in adult patients with

persistent cough.

Ahmad R(1), Xie L(2)(3)(4), Pyle M(5), Suarez MF(6), Broger T(7), Steinberg D(8),

Ame SM(9), Lucero MG(10), Szucs MJ(11), MacMullan M(11), Berven FS(12), Dutta

A(13), Sanvictores DM(10), Tallo VL(10), Bencher R(14), Eisinger DP(14), Dhingra

U(13), Deb S(13), Ali SM(9), Mehta S(15), Fawzi WW(16), Riley ID(17), Sazawal

S(13), Premji Z(18), Black R(19), Murray CJL(20), Rodriguez B(21), Carr SA(11),

Walt DR(22)(3)(4), Gillette MA(1)(23).

Author information:

(1)Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.

dwalt@bwh.harvard.edu qrushdy@gmail.com gillette@broadinstitute.org.

...

Erratum in

Sci Transl Med. 2019 Oct 30;11(516):.

Improved tuberculosis (TB) prevention and control depend critically on the

development of a simple, readily accessible rapid triage test to stratify TB

risk. We hypothesized that a blood protein-based host response signature for

active TB (ATB) could distinguish it from other TB-like disease (OTD) in adult

patients with persistent cough, thereby providing a foundation for a

point-of-care (POC) triage test for ATB. Three adult cohorts consisting of ATB

suspects were recruited. A bead-based immunoassay and machine learning algorithms

identified a panel of four host blood proteins, interleukin-6 (IL-6), IL-8,

IL-18, and vascular endothelial growth factor (VEGF), that distinguished ATB from

OTD. An ultrasensitive POC-amenable single-molecule array (Simoa) panel was

configured, and the ATB diagnostic algorithm underwent blind validation in an

independent, multinational cohort in which ATB was distinguished from OTD with

receiver operator characteristic-area under the curve (ROC-AUC) of 0.80 [95%

confidence interval (CI), 0.75 to 0.85], 80% sensitivity (95% CI, 73 to 85%), and

65% specificity (95% CI, 57 to 71%). When host antibodies against TB antigen

Ag85B were added to the panel, performance improved to 86% sensitivity and 69%

specificity. A blood-based host response panel consisting of four proteins and

antibodies to one TB antigen can help to differentiate ATB from other causes of

persistent cough in patients with and without HIV infection from Africa, Asia,

and South America. Performance characteristics approach World Health Organization

(WHO) target product profile accuracy requirements and may provide the foundation

for an urgently needed blood-based POC TB triage test.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/scitranslmed.aaw8287

PMID: 31645455

7. Nat Commun. 2019 Oct 11;10(1):4639. doi: 10.1038/s41467-019-12614-7.

Acetyl-CoA-mediated activation of Mycobacterium tuberculosis isocitrate lyase 2.

Bhusal RP(1), Jiao W(2)(3), Kwai BXC(1), Reynisson J(1)(4), Collins AJ(1), Sperry

J(5), Bashiri G(6)(7), Leung IKH(8)(9).

Author information:

(1)School of Chemical Sciences, The University of Auckland, Private Bag 92019,

Victoria Street West, Auckland, 1142, New Zealand.

...

Isocitrate lyase is important for lipid utilisation by Mycobacterium tuberculosis

but its ICL2 isoform is poorly understood. Here we report that binding of the

lipid metabolites acetyl-CoA or propionyl-CoA to ICL2 induces a striking

structural rearrangement, substantially increasing isocitrate lyase and

methylisocitrate lyase activities. Thus, ICL2 plays a pivotal role regulating

carbon flux between the tricarboxylic acid (TCA) cycle, glyoxylate shunt and

methylcitrate cycle at high lipid concentrations, a mechanism essential for

bacterial growth and virulence.

DOI: 10.1038/s41467-019-12614-7

PMCID: PMC6788997

PMID: 31604954

8. PLoS Med. 2019 Oct 4;16(10):e1002891. doi: 10.1371/journal.pmed.1002891.

eCollection 2019 Oct.

Wirelessly observed therapy compared to directly observed therapy to confirm and

support tuberculosis treatment adherence: A randomized controlled trial.

Browne SH(1), Umlauf A(1), Tucker AJ(1), Low J(2), Moser K(3), Gonzalez Garcia

J(1), Peloquin CA(4), Blaschke T(5), Vaida F(1), Benson CA(1).

Author information:

(1)University of California San Diego, La Jolla, California, United States of

America.

(2)Orange County Health Care Agency, Santa Ana, California, United States of

America.

(3)Health and Human Services Agency, San Diego, California, United States of

America.

(4)University of Florida, Gainesville, Florida, United States of America.

(5)Stanford University, Stanford, California, United States of America.

BACKGROUND: Excellent adherence to tuberculosis (TB) treatment is critical to

cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT)

is a novel patient self-management system consisting of an edible ingestion

sensor (IS), external wearable patch, and paired mobile device that can detect

and digitally record medication ingestions. Our study determined the accuracy of

ingestion detection in clinical and home settings using WOT and subsequently

compared, in a randomized control trial (RCT), confirmed daily adherence to

medication in persons using WOT or directly observed therapy (DOT) during TB

treatment.

METHODS AND FINDINGS: We evaluated WOT in persons with active Mycobacterium

tuberculosis complex disease using IS-enabled combination isoniazid 150

mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with

drug-susceptible TB in the continuation phase of treatment, prescribed daily

isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of

the trial were determination of the positive detection accuracy (PDA) of WOT,

defined as the percentage of ingestions detected by WOT administered under direct

observation, and subsequently the proportion of prescribed doses confirmed by WOT

compared to DOT. Initially participants received DOT and WOT simultaneously for

2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI)

was estimated using the bootstrap method with 10,000 samples. Sixty-one

participants subsequently participated in an RCT to compare the proportion of

prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to

receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not

remotely confirmed, the participant was contacted within 24 hours by text or cell

phone to provide support. The number of doses confirmed was collected, and

nonparametric methods were used for group and individual comparisons to estimate

the proportions of confirmed doses in each randomized arm with 95% CIs.

Sensitivity analyses, not prespecified in the trial registration, were also

performed, removing all nonworking (weekend and public holiday) and held-dose

days. Participants, recruited from San Diego (SD) and Orange County (OC)

Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old,

57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT

was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed

WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary

analysis removing all nonworking days (weekends and public holidays) and held

doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was

non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of

participants preferred using WOT. WOT associated adverse events were <10%,

consisting of minor skin rash and pruritus associated with the patch. WOT

provided longitudinal digital reporting in near real time, supporting patient

self-management and allowing rapid remote identification of those who needed more

support to maintain adherence. This study was conducted during the continuation

phase of TB treatment, limiting its generalizability to the entire TB treatment

course.

CONCLUSIONS: In terms of accuracy, WOT was equivalent to DOT. WOT was superior to

DOT in supporting confirmed daily adherence to TB medications during the

continuation phase of TB treatment and was overwhelmingly preferred by

participants. WOT should be tested in high-burden TB settings, where it may

substantially support low- and middle-income country (LMIC) TB programs.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01960257.

DOI: 10.1371/journal.pmed.1002891

PMCID: PMC6777756

PMID: 31584944

9. Lancet Infect Dis. 2019 Oct;19(10):1129-1137. doi: 10.1016/S1473-3099(19)30309-3.

Epub 2019 Jul 16.

Long-term all-cause mortality in people treated for tuberculosis: a systematic

review and meta-analysis.

Romanowski K(1), Baumann B(2), Basham CA(3), Ahmad Khan F(4), Fox GJ(5), Johnston

JC(6).

Author information:

(1)Provincial TB Services, British Columbia Centre for Disease Control,

Vancouver, BC, Canada.

...

BACKGROUND: Accurate estimates of long-term mortality following tuberculosis

treatment are scarce. This systematic review and meta-analysis aimed to estimate

the post-treatment mortality among tuberculosis survivors, and examine

differences in mortality risk by demographic and clinical characteristics.

METHODS: We systematically searched Embase, MEDLINE, and the Cochrane Database of

Systematic Reviews for cohort studies published in English between Jan 1, 1997,

and May 31, 2018. We included research papers that used a cohort study design,

included bacteriological or clinical confirmation of tuberculosis disease for all

participants, and reported, or provided enough data to calculate, mortality

estimates for people with tuberculosis and a valid control group representative

of the general population. We excluded studies that reported duplicate data, had

a study population of fewer than 50 people overall, had a follow-up period

shorter than 12 months after treatment completion, or had a loss to follow-up of

more than 30%. From eligible studies, we extracted standardised mortality ratios

(SMRs), or calculated them when the data were sufficient, by dividing the sum of

the observed deaths by the sum of the expected deaths. For studies that did not

report SMR as their mortality estimate, either mortality hazard ratios or

mortality rate ratios were extracted and pooled with SMRs. Random-effects

meta-analysis was used to obtain pooled SMRs. Between-study heterogeneity was

estimated with I2. This study was prospectively registered in PROSPERO

(CRD42018092592).

FINDINGS: Of the 7283 unique studies identified, data from ten studies, reporting

on 40?781 individuals and 6922 deaths, were included. The pooled SMR for

all-cause mortality among people with tuberculosis, compared with the control

group, was 2·91 (95% CI 2·21-3·84; I2=99%, pheterogeneity<0·0001). When

restricted to people with confirmed treatment completion or cure, the pooled SMR

was 3·76 (95% CI 3·04-4·66; I2=95%). Effect estimates were similar when

stratified by tuberculosis type, sex, age, and country income category. Causes of

mortality were extracted for 4226 deaths that occurred post-treatment, with most

deaths attributable to cardiovascular disease (20% [95% CI 15-26]; I2=92%).

INTERPRETATION: People treated for tuberculosis have significantly increased

mortality following treatment compared with the general population or matched

controls. These findings support the need for further research to understand and

address the biomedical and social factors that affect the long-term prognosis of

this population.

FUNDING: None.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(19)30309-3

PMID: 31324519

10. Chem Sci. 2019 Aug 6;10(38):8764-8767. doi: 10.1039/c9sc02520k. eCollection 2019

Oct 14.

Discovery of small-molecule inhibitors targeting the ribosomal peptidyl

transferase center (PTC) of M. tuberculosis.

Tam B(1), Sherf D(1), Cohen S(1), Eisdorfer SA(1), Perez M(2), Soffer A(3),

Vilenchik D(3), Akabayov SR(2), Wagner G(4), Akabayov B(1).

Author information:

(1)Department of Chemistry , Ben-Gurion University of the Negev , Beer-Sheva ,

Israel . Email: akabayov@bgu.ac.il.

(2)Department of Structural Biology , Weizmann Institute of Science , Rehovot ,

Israell.

(3)School of Computer and Electrical Engineering , Ben-Gurion University of the

Negev , Israel.

(4)Department of Biological Chemistry and Molecular Pharmacology , Harvard

Medical School , Boston , MA , USA.

M. tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis, which

kills more than 1.5 million people worldwide every year. Strains resistant to

available antibiotics pose a significant healthcare problem. The enormous

complexity of the ribosome poses a barrier for drug discovery. We have overcome

this in a tractable way by using an RNA segment that represents the peptidyl

transferase center as a target. By using a novel combination of NMR transverse

relaxation times (T 2) and computational chemistry approaches, we have obtained

improved inhibitors of the Mtb ribosomal PTC. Two phenylthiazole derivatives were

predicted by machine learning models as effective inhibitors, and this was

confirmed by their IC50 values, which were significantly improved over standard

antibiotic drugs.

This journal is © The Royal Society of Chemistry 2019.

DOI: 10.1039/c9sc02520k

PMCID: PMC6849635

PMID: 31803448

11. J Infect Dis. 2019 Oct 31. pii: jiz541. doi: 10.1093/infdis/jiz541. [Epub ahead

of print]

Nicotinamide limits replication of Mycobacterium tuberculosis and BCG within

macrophages.

Simmons JD(1), Peterson GJ(1), Campo M(1), Lohmiller J(2), Skerrett SJ(3), Tunaru

S(4), Offermanns S(4), Sherman DR(2)(5), Hawn TR(1).

Author information:

(1)TB Research & Training Center, Department of Medicine, University of

Washington, Seattle, WA, USA.

(2)Center for Global Infectious Disease Research, Seattle Children's Research

Institute, Seattle, WA, USA.

(3)Division of Pulmonary, Critical Care and Sleep Medicine, Department of

Medicine, University of Washington, Seattle, WA, USA.

(4)Department of Pharmacology, Max Planck Institute for Heart and Lung Research,

Bad Nauheim, Germany.

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

Novel antimicrobials for treatment of Mycobacterium tuberculosis (Mtb) are

needed. We hypothesized that nicotinamide (NAM) and nicotinic acid (NA) modulate

macrophage function to restrict Mtb replication in addition to their direct

antimicrobial properties. Both compounds had modest activity in 7H9 broth, but

only NAM inhibited replication in macrophages. Surprisingly, in macrophages NAM

and the related compound pyrazinamide (PZA) restricted growth of BCG but not

wild-type M.bovis, which both lack a functional PncA amidase rendering each

strain resistant to these drugs in broth culture. Interestingly, NAM was not

active in macrophages infected with a virulent Mtb mutant encoding a deletion in

pncA. We conclude that the differential activity of NAM and NA on infected

macrophages suggests host-specific NAM targets that are associated with M. bovis

strain virulence rather than PncA-dependent direct antimicrobial properties.

These activities are sufficient to restrict attenuated BCG, but not virulent

wild-type M. bovis or Mtb.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America.

DOI: 10.1093/infdis/jiz541

PMID: 31665359

12. J Infect Dis. 2019 Oct 23. pii: jiz546. doi: 10.1093/infdis/jiz546. [Epub ahead

of print]

Evolution of antibodies to epitopes of PE_PGRS51 in the spectrum of active

pulmonary tuberculosis.

Sakamuri RM(1), Singh KK(1), Ryndak MB(1), Laal S(1)(2).

Author information:

(1)Department of Pathology, New York University Langone Medical Center, New York,

USA.

(2)Veterans Affairs Medical Center, New York Harbor Health Care System, New York,

USA.

BACKGROUND: The PE_PGRS protein family isimplicated in virulence and

immunopathogenesis of M. tuberculosis. Due to extensive intra-family homology, it

has not been possible to correlate expression of specific members with stage of

infection or disease progression. Here, we investigate the in vivo expression of

PE_PGRS51, which besides the cross-reactive PE and PGRS domains, has 3 unique

regions.

METHODS: Expression in M. smegmatis confirmed PE_PGRS51 cell-wall localization.

Patients at different stages of TB were classified across a spectrum akin to the

Leprosy spectrum. Peptide arrays representing PE_PGRS51 were screened with sera

from TB patients across the spectrum of active TB, with latent TB sera as

controls.

RESULTS: Antibodies directed only against conserved epitopes within the PE/PGRS

domains were detectable at early stages of TB. As bacteriological burden and

disease progresses, the epitope repertoire extends systematically to adjacent and

overlapping peptides. Sera-reactivity to epitopes unique to PE_PGRS51 appear only

in the most advanced TB patients, indicating PE_PGRS51 expression in vivo.

DISCUSSION: The ability to classify active TB patients into a spectrum and

delineate the in vivo expression of PE_PGRS proteins at different stages of

disease has important implications for understanding their role in TB

pathogenesis and their usefulness as diagnostic markers.

© The Author(s) 2019. 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/infdis/jiz546

PMID: 31641771

13. Eur Respir J. 2019 Oct 16. pii: 1901181. doi: 10.1183/13993003.01181-2019. [Epub

ahead of print]

A regimen containing bedaquiline and delamanid compared to bedaquiline in

patients with drug resistant tuberculosis.

Olayanju O(1), Esmail A(1), Limberis J(1), Dheda K(2)(3).

Author information:

(1)Centre for Lung Infection and Immunity, Department of Medicine and UCT Lung

Institute, Division of Pulmonology, University of Cape Town, Cape Town, South

Africa.

(2)Centre for Lung Infection and Immunity, Department of Medicine and UCT Lung

Institute, Division of Pulmonology, University of Cape Town, Cape Town, South

Africa keertan.dheda@uct.ac.za.

(3)Faculty of Infectious and Tropical Diseases, Department of Immunology and

Infection, London School of Hygiene and Tropical Medicine, London, UK.

There are limited data about combining delamanid and bedaquiline in

drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data,

including in HIV-infected persons, are unavailable.We prospectively followed up

122 South Africans (52.5% HIV-infected) with DR-TB and poor prognostic features

between 2014 and 2018. We compared outcomes and safety in those who received a

bedaquiline-based regimen (n=82) to those who received a bedaquiline-delamanid

combination regimen (n=40).There was no significant difference in 6-month culture

conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate

(63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline-delamanid

combination group, despite the latter having more advanced drug resistance (3.7%

versus 22.5% resistant >5 drugs; p=0.001) and higher pre-treatment failure rates

(12.2% versus 52.5% with pre-treatment MDR-TB therapy failure; p<0.001). Although

the proportion of QTcF prolongation was higher in the combination group [>60?ms

from baseline (p=0.001) or >450?ms during treatment (p=0.001)], there were no

symptomatic cases or drug withdrawal in either group. Results were similar in

HIV-infected patients.A bedaquiline-delamanid combination regimen showed

comparable long-term safety, to a bedaquiline-based regimen, in patients with

DR-TB irrespective of HIV status. These data inform regimen selection in patients

with DR-TB from TB endemic settings.

Copyright ©ERS 2019.

DOI: 10.1183/13993003.01181-2019

PMID: 31619478

14. Bioinformatics. 2019 Oct 3. pii: btz729. doi: 10.1093/bioinformatics/btz729.

[Epub ahead of print]

Towards next-generation diagnostics for tuberculosis: identification of novel

molecular targets by large-scale comparative genomics.

Goig GA(1), Torres-Puente M(1), Mariner-Llicer C(1), Villamayor LM(2), Chiner-Oms

Á(1), Gil-Brusola A(3), Borrás R(4)(5), Comas I(1)(6).

Author information:

(1)Institute of Biomedicine of Valencia (CSIC), Valencia, Spain.

(2)FISABIO Public Health (CSISP), Valencia, Spain.

(3)La Fe University and Polytechnic Hospital, Valencia, Spain.

(4)University Clinic Hospital, Valencia, Spain.

(5)School of Medicine, University of Valencia, Valencia, Spain.

(6)CIBER in Epidemiology and Public Health, Madrid, Spain.

MOTIVATION: Tuberculosis remains one of the main causes of death worldwide. The

long and cumbersome process of culturing Mycobacterium tuberculosis complex

(MTBC) bacteria has encouraged the development of specific molecular tools for

detecting the pathogen. Most of these tools aim to become novel tuberculosis

diagnostics, and big efforts and resources are invested in their development,

looking for the endorsement of the main public health agencies. Surprisingly, no

study had been conducted where the vast amount of genomic data available is used

to identify the best MTBC diagnostic markers.

RESULTS: In this work, we used large-scale comparative genomics to identify 40

MTBC-specific loci. We assessed their genetic diversity and physiological

features to select 30 that are good targets for diagnostic purposes. Some of

these markers could be used to assess the physiological status of the bacilli.

Remarkably, none of the most used MTBC markers is in our catalog. Illustrating

the translational potential of our work, we develop a specific qPCR assay for

quantification and identification of MTBC DNA. Our rational design of targeted

molecular assays for tuberculosis could be used in many other fields of clinical

and basic research.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics

online.

© The Author(s) 2019. Published by Oxford University Press.

DOI: 10.1093/bioinformatics/btz729

PMID: 31580405

15. ACS Appl Mater Interfaces. 2019 Oct 2;11(39):35622-35629. doi:

10.1021/acsami.9b15248. Epub 2019 Sep 24.

Graphdiyne-Based One-Step DNA Fluorescent Sensing Platform for the Detection of

Mycobacterium tuberculosis and Its Drug-Resistant Genes.

Chang F(1), Huang L(1), Guo C(2), Xie G(3), Li J(4), Diao Q(1).

Author information:

(1)Central Laboratory of Yongchuan Hospital , Chongqing Medical University ,

Chongqing 402160 , China.

(2)Research Institute for New Materials Technology , Chongqing University of Arts

and Sciences , Chongqing 402160 , China.

(3)Key Laboratory of Laboratory Medical Diagnostics of Education , Chongqing

Medical University , Chongqing 400016 , China.

(4)School of Chemistry and Chemical Engineering , Chongqing University ,

Chongqing 400044 , China.

The accurate and early detection of Mycobacterium tuberculosis (Mtb) is of great

significance for the clinical diagnosis and treatment of tuberculosis. In this

work, we report a facile method for the controllable synthesis of a novel

few-layered two-dimensional graphdiyne nanosheet (GDY NS) with a thickness of

only ∼0.9 nm via an electrochemical lithium-intercalation strategy, which

possesses a prominent fluorescence quenching effect. The few-layered GDY NS with

its strong adsorptivity for single-stranded DNA is first proposed as a new

fluorescent sensing platform for the real-time detection of DNA with excellent

specificity, multiplicity, and superhigh sensitivity (limit of detection as low

as 25 pM). This sensing platform can be further applied for the Mtb detection

from clinical samples and the identification of drug-resistant mutants with a low

background and a high signal-to-noise ratio. Herein, we provide a potential basis

for the clinical development of rapid, sensitive, and accurate substitutes for

the molecular diagnosis of Mtb and its drug-resistant genes.

DOI: 10.1021/acsami.9b15248

PMID: 31502436

16. Eur Respir J. 2019 Oct 10;54(4). pii: 1900982. doi: 10.1183/13993003.00982-2019.

Print 2019 Oct.

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018

WHO guidance.

Stagg HR(1)(2), Bothamley GH(3)(4), Davidson JA(5)(4), Kunst H(6)(4), Lalor

MK(7)(5)(4), Lipman MC(8)(9)(4), Loutet MG(5)(4), Lozewicz S(10)(4), Mohiyuddin

T(5)(4), Abbara A(11)(4), Alexander E(12)(4), Booth H(13)(4), Creer DD(14)(4),

Harris RJ(15)(4), Kon OM(16)(4), Loebinger MR(17)(4), McHugh TD(18)(4), Milburn

HJ(19)(4), Palchaudhuri P(20)(4), Phillips PPJ(21)(4), Schmok E(3)(4), Taylor

L(12)(4), Abubakar I(7); London INH-R TB study group.

Collaborators: Baker LV, Barrett JC, Burgess H, Cosgrove C, Dunleavy A, Francis

M, Gupta U, Hamid S, Haselden BM, Holden E, Kahr V, Lynn W, Perrin FM, Rahman A,

Soobratty MR.

Author information:

(1)Institute for Global Health, University College London, London, UK

helen.stagg@ed.ac.uk.

...

Comment in

Eur Respir J. 2019 Oct 10;54(4):.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment

of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen:

rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or

without H ([H]RZE-Lfx). This is used once Hr is known, such that patients

complete 6?months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact

of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations

and degree of phenotypic resistance.

METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients

notified in London, 2009-2013. Regimens were described and logistic regression

undertaken of the association between regimen and negative regimen-specific

outcomes (broadly, death due to tuberculosis, treatment failure or disease

recurrence).

RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated

with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall

treatment period was 11.9?months and median Z duration 2.1?months. In a

univariable logistic regression model comparing (H)RfZE with and without Fqs,

there was no difference in the odds of a negative regimen-specific outcome

(baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87;

cluster NHS trust). Results varied minimally in a multivariable model. This odds

ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this

analysis lacked power (p=0.42).

CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a

short Z duration to be similarly effective for Hr tuberculosis with or without a

Fq. This regimen may result in fewer adverse events than the WHO recommendations.

Copyright ©ERS 2019.

DOI: 10.1183/13993003.00982-2019

PMCID: PMC6785706

PMID: 31371444

17. Clin Infect Dis. 2019 Oct 15;69(9):1631-1633. doi: 10.1093/cid/ciz219.

Building the Framework for Standardized Clinical Laboratory Reporting of

Next-generation Sequencing Data for Resistance-associated Mutations in

Mycobacterium tuberculosis Complex.

Tornheim JA(1), Starks AM(2), Rodwell TC(3)(4), Gardy JL(5)(6), Walker TM(7),

Cirillo DM(8), Jayashankar L(9), Miotto P(8), Zignol M(10), Schito M(11).

Author information:

(1)Division of Infectious Diseases, Johns Hopkins University School of Medicine,

Baltimore, Maryland.

...

Tuberculosis is the primary infectious disease killer worldwide, with a growing

threat from multidrug-resistant cases. Unfortunately, classic growth-based

phenotypic drug susceptibility testing (DST) remains difficult, costly, and time

consuming, while current rapid molecular testing options are limited by the

diversity of antimicrobial-resistant genotypes that can be detected at once.

Next-generation sequencing (NGS) offers the opportunity for rapid, comprehensive

DST without the time or cost burden of phenotypic tests and can provide useful

information for global surveillance. As access to NGS expands, it will be

important to ensure that results are communicated clearly, consistent, comparable

between laboratories, and associated with clear guidance on clinical

interpretation of results. In this viewpoint article, we summarize 2 expert

workshops regarding a standardized report format, focusing on relevant variables,

terminology, and required minimal elements for clinical and laboratory reports

with a proposed standardized template for clinical reporting NGS results for

Mycobacterium tuberculosis.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America.

DOI: 10.1093/cid/ciz219

PMCID: PMC6792097

PMID: 30883637