#Chemical disarming of #isoniazid resistance in #Mycobacterium tuberculosis (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy  of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis

Kelly Flentie, Gregory A. Harrison, Hasan Tükenmez, Jonathan Livny, James A. D. Good, Souvik Sarkar, Dennis X. Zhu, Rachel L. Kinsella, Leslie A. Weiss, Samantha D. Solomon, Miranda E. Schene, Mette R. Hansen, Andrew G. Cairns, Martina Kulén, Torbjörn Wixe, Anders E. G. Lindgren, Erik Chorell, Christoffer Bengtsson, K. Syam Krishnan, Scott J. Hultgren, Christer Larsson, Fredrik Almqvist, and Christina L. Stallings

PNAS first published May 6, 2019 / DOI: https://doi.org/10.1073/pnas.1818009116

Edited by Caroline S. Harwood, University of Washington, Seattle, WA, and approved April 5, 2019 (received for review October 22, 2018)

 

Significance

Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis (TB), which kills more people than any other infection. The emergence of drug-resistant Mtb strains has exacerbated this already alarming epidemic. We have identified a small molecule, C10, that potentiates the activity of the frontline antibiotic isoniazid (INH) and prevents the selection for INH-resistant mutants. We find that C10 can even reverse INH resistance in Mtb. Therefore, our study reveals vulnerabilities that can be exploited to reverse INH resistance in Mtb.

 

Abstract

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Mycobacterium tuberculosis – drug tolerance – antibiotic resistance – isoniazid – respiration

 

Footnotes

1 K.F. and G.A.H. contributed equally to this work.

2 To whom correspondence may be addressed. Email: fredrik.almqvist@umu.se or stallings@wustl.edu.

Author contributions: K.F., G.A.H., and C.L.S. designed research; K.F., G.A.H., H.T., J.L., D.X.Z., R.L.K., L.A.W., S.D.S., M.E.S., and C.L. performed research; J.L., J.A.D.G., S.S., M.R.H., A.G.C., M.K., T.W., A.E.G.L., E.C., C.B., K.S.K., and F.A. contributed new reagents/analytic tools; K.F., G.A.H., H.T., J.L., J.A.D.G., D.X.Z., R.L.K., L.A.W., S.D.S., M.E.S., S.J.H., C.L., F.A., and C.L.S. analyzed data; and K.F., G.A.H., and C.L.S. wrote the paper.

Conflict of interest statement: C.L.S., S.J.H., and F.A. have ownership interests in Quretech Bio AB, which licenses C10.

This article is a PNAS Direct Submission.

Data Deposition: The RNA-sequencing data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE129835).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818009116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Tuberculosis; Antibiotics; Drugs Resistance; Isoniazid.

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Extensive #global #movement of #MDR M. #tuberculosis strains revealed by whole-genome analysis (Thorax, abstract)

[Source: Thorax, full page: (LINK). Abstract, edited.]

Extensive global movement of multidrug-resistant M. tuberculosisstrains revealed by whole-genome analysis

Keira A Cohen 1, Abigail L Manson 2, Thomas Abeel 2,3, Christopher A Desjardins 2, Sinead B Chapman 2, Sven Hoffner 4, Bruce W Birren 2, Ashlee M Earl 2

Author affiliations: 1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 2 Broad Institute of Harvard and M.I.T, Cambridge, Massachusetts, USA; 3 Delft Bioinformatics Lab, Technische Universiteit Delft Faculteit Technische Natuurwetenschappen, Delft, Netherlands; 4 Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden

Correspondence to Dr Ashlee M Earl, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; aearl@broadinstitute.org

 

Abstract

Background 

While the international spread of multidrug-resistant (MDR) Mycobacterium tuberculosis strains is an acknowledged public health threat, a broad and more comprehensive examination of the global spread of MDR-tuberculosis (TB) using whole-genome sequencing has not yet been performed.

Methods 

In a global dataset of 5310 M. tuberculosis whole-genome sequences isolated from five continents, we performed a phylogenetic analysis to identify and characterise clades of MDR-TB with respect to geographic dispersion.

Results 

Extensive international dissemination of MDR-TB was observed, with identification of 32 migrant MDR-TB clades with descendants isolated in 17 unique countries. Relatively recent movement of strains from both Beijing and non-Beijing lineages indicated successful global spread of varied genetic backgrounds. Migrant MDR-TB clade members shared relatively recent common ancestry, with a median estimate of divergence of 13–27 years. Migrant extensively drug-resistant (XDR)-TB clades were not observed, although development of XDR-TB within migratory MDR-TB clades was common.

Conclusions 

Application of genomic techniques to investigate global MDR migration patterns revealed extensive global spread of MDR clades between countries of varying TB burden. Further expansion of genomic studies to incorporate isolates from diverse global settings into a single analysis, as well as data sharing platforms that facilitate genomic data sharing across country lines, may allow for future epidemiological analyses to monitor for international transmission of MDR-TB. In addition, efforts to perform routine whole-genome sequencing on all newly identified M. tuberculosis, like in England, will serve to better our understanding of the transmission dynamics of MDR-TB globally.

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

DOI: http://dx.doi.org/10.1136/thoraxjnl-2018-211616

Keywords: Antibiotics; Drugs Resistance; MDR-TB; Tuberculosis.

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#Tuberculosis as a #Risk #Factor for 1918 #Influenza #Pandemic #Outcomes (Trop Med Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Trop Med Infect Dis. 2019 Apr 29;4(2). pii: E74. doi: 10.3390/tropicalmed4020074.

Tuberculosis as a Risk Factor for 1918 Influenza Pandemic Outcomes.

Mamelund SE1, Dimka J2.

Author information: 1 Work Research Institute, OsloMet-Oslo Metropolitan University, PO. Box 4, St. Olavs Plass, 0130 Oslo, Norway. masv@oslomet.no. 2 Department of Anthropology, University of Pittsburgh, Pittsburgh, PA 15260, USA. jld199@pitt.edu.

 

Abstract

Tuberculosis (TB) mortality declined after the 1918 pandemic, suggesting that influenza killed those who would have died from TB. Few studies have analyzed TB as a direct risk factor for 1918 influenza morbidity and mortality by age and sex. We study the impacts of TB on influenza-like illness (% of population sick) and case fatality (% of cases dying) by age and sex through case-control comparisons of patients (N = 201) and employees (N = 97) from two Norwegian sanatoriums. Female patients, patients at Landeskogen sanatorium, and patients aged 10-39 years had significantly lower morbidity than the controls. None of the 62 sick employees died, while 15 of 84 sick patients did. The case-control difference in case fatality by sex was only significant for females at Lyster sanatorium and females at both sanatoriums combined. Non-significant case-control differences in case fatality for males were likely due to small samples. Patients 20-29 years for both sexes combined at Lyster sanatorium and at both sanatoriums combined, as well as females 20-29 years for both sanatoriums combined, had significantly higher case fatality. We conclude that TB was associated with higher case fatality, but morbidity was lower for patients than for employees. The results add to the study of interactions between bacterial and viral diseases and are relevant in preparing for pandemics in TB endemic areas.

KEYWORDS: 1918 pandemic; Spanish flu; case fatality; case-control studies; historical epidemiology; morbidity; tuberculosis and influenza interactions

PMID: 31035651 DOI: 10.3390/tropicalmed4020074

Keywords: Pandemic Influenza; H1N1; Spanish Flu; Tuberculosis; Norway.

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#Urban #airborne #particle exposure impairs #human #lung and blood Mycobacterium #tuberculosis #immunity (Thorax, abstract)

[Source: Thorax, full page: (LINK). Abstract, edited.]

Urban airborne particle exposure impairs human lung and blood Mycobacterium tuberculosis immunity

Martha Torres 1, Claudia Carranza 1, Srijata Sarkar 2, Yolanda Gonzalez 1, Alvaro Osornio Vargas 3, Kathleen Black 4, Qingyu Meng 2, Raul Quintana-Belmares 5, Martha Hernandez 6, Jose Juan F Angeles Garcia 6, Victor Hugo Páramo-Figueroa 6, Marco Antonio Iñiguez-Garcia 7, Jose L Flores 8, Junfeng (Jim) Zhang 9, Carol R Gardner 10, Pamela Ohman-Strickland 11, Stephan Schwander 12

Author affiliations: 1 Department of Microbiology, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; 2 Environmental and Occupational Health, Rutgers School of Public Health New Brunswick Campus, Piscataway, New Jersey, USA; 3 Paediatrics, University of Alberta, Edmonton, Alberta, Canada; 4 Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA; 5 Investigacion basica, Instituto Nacional de Cancerologia, Mexico City, Mexico; 6 Contaminacion y salud ambiental, Instituto Nacional de Ecologia y Cambio Climatico, Coyoacan, Mexico; 7 Department of Thoracic Surgery, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; 8 Departamento de ciencias de la salud, Universidad Autonoma Metropolitana Iztapalapa, Iztapalapa, Mexico; 9 Duke Global Health Institute and Nicholas School of the Environment, Duke University, Durham, North Carolina, USA; 10 Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, USA; 11 Biostatistics, Rutgers School of Public Health New Brunswick Campus, Piscataway, New Jersey, USA; 12 Urban-Global Public Health and Environmental and Occupational Health, Rutgers School of Public Health New Brunswick Campus, Piscataway, New Jersey, USA

Correspondence to Dr Stephan Schwander, Departments of Urban-Global Public Health and Environmental and Occupational Health, Rutgers School of Public Health, Newark Campus, Newark, NJ 07102, USA; schwansk@sph.rutgers.edu

 

Abstract

Rationale 

Associations between urban (outdoor) airborne particulate matter (PM) exposure and TB and potential biological mechanisms are poorly explored.

Objectives 

To examine whether in vivo exposure to urban outdoor PM in Mexico City and in vitro exposure to urban outdoor PM2.5(< 2.5 µm median aerodynamic diameter) alters human host immune cell responses to Mycobacterium tuberculosis.

Methods 

Cellular toxicity (flow cytometry, proliferation assay (MTS assay)), M. tuberculosis and PM2.5 phagocytosis (microscopy), cytokine-producing cells (Enzyme-linked immune absorbent spot (ELISPOT)), and signalling pathway markers (western blot) were examined in bronchoalveolar cells (BAC) and peripheral blood mononuclear cells (PBMC) from healthy, non-smoking, residents of Mexico City (n=35; 13 female, 22 male). In vivo-acquired PM burden in alveolar macrophages (AM) was measured by digital image analysis.

Measurements and main results 

In vitro exposure of AM to PM2.5 did not affect M. tuberculosis phagocytosis. High in vivo-acquired AM PM burden reduced constitutive, M. tuberculosis and PM-induced interleukin-1β production in freshly isolated BAC but not in autologous PBMC while it reduced constitutive production of tumour necrosis factor-alpha in both BAC and PBMC. Further, PM burden was positively correlated with constitutive, PM, M. tuberculosis and purified protein derivative (PPD)-induced interferon gamma (IFN-γ) in BAC, and negatively correlated with PPD-induced IFN-γ in PBMC.

Conclusions 

Inhalation exposure to urban air pollution PM impairs important components of the protective human lung and systemic immune response against M. tuberculosis. PM load in AM is correlated with altered M. tuberculosis-induced cytokine production in the lung and systemic compartments. Chronic PM exposure with high constitutive expression of proinflammatory cytokines results in relative cellular unresponsiveness.

DOI: http://dx.doi.org/10.1136/thoraxjnl-2018-212529

Keywords: Environmental pollution; Tuberculosis; Immunopathology.

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#Tuberculosis in #diabetes: insidious and neglected (Lancet Resp Med., summary)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Tuberculosis in diabetes: insidious and neglected

Ammara Mushtaq

Published: April 16, 2019 / DOI: https://doi.org/10.1016/S2213-2600(19)30119-5

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In October, 2018, the International Union Against Tuberculosis and Lung Disease (The Union) and The World Diabetes Foundation released the first edition of new guidelines pertaining to the treatment of patients with concurrent tuberculosis and diabetes. “These are the first global guidelines on how to screen for and manage people with diabetes-tuberculosis…They are holistic and also include advice about infection control in diabetes clinics, recording and reporting, and about how to set up joint collaboration in the ministries of health”, says Anthony Harries (The Union, London, UK).
These guidelines state that patients with newly diagnosed diabetes should be systematically screened for tuberculosis in countries with a high burden of the disease, where prevalence is greater than 100 cases per 100 000 patients. Likewise, they state that all patients with tuberculosis should be screened for diabetes.

(…)

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Article Info

Publication History: Published: April 16, 2019

Identification: DOI: https://doi.org/10.1016/S2213-2600(19)30119-5

Copyright © 2019 Elsevier Ltd. All rights reserved.

Keywords: Tuberculosis; Diabetes.

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#Outcomes of #Bedaquiline #Treatment in Patients with #MDR #Tuberculosis (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 5—May 2019 / Research

Outcomes of Bedaquiline Treatment in Patients with Multidrug-Resistant Tuberculosis

Lawrence Mbuagbaw  , Lorenzo Guglielmetti, Catherine Hewison, Nyasha Bakare, Mathieu Bastard, Eric Caumes, Mathilde Fréchet-Jachym, Jérôme Robert, Nicolas Veziris, Naira Khachatryan, Tinatin Kotrikadze, Armen Hayrapetyan, Zaza Avaliani, Holger J. Schünemann, and Christian Lienhardt

Author affiliations: St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada (L. Mbuagbaw); Centre for the Development of Best Practices in Health, Yaoundé, Cameroon (L. Mbuagbaw); McMaster University, Hamilton (L. Mbuagbaw, H.J. Schünnemann); Centre d’Immunologie et des Maladies Infectieuses, INSERM, Paris (L. Guglielmetti, E. Caumes, J. Robert, N. Veziris); Centre Hospitalier de Bligny, Bris-sous-Forges, France (L. Guglielmetti, M. Frechet-Jachym); Sorbonne Université, Paris, France (L. Guglielmetti, J. Robert, N. Veziris); Médecins Sans Frontières, Paris (C. Hewison); Janssen Research & Development, LLC, Titusville, New Jersey, USA (N. Bakere); Epicentre, Paris (M. Bastard); Hôpitaux Universitaires de l’Est Parisien, Paris (N. Veziris); Médecins Sans Frontières, Yerevan, Armenia (N. Khachatryan); Médecins Sans Frontières, Tbilisi, Georgia (T. Kotrikadze); National Tuberculosis Control Centre, Yerevan (A. Hayrapetyan); National Centre for Tuberculosis and Lung Disease, Tbilisi (Z. Avaliani); World Health Organization, Geneva, Switzerland (C. Lienhardt); Université de Montpellier, Montpellier, France (C. Lienhardt)

 

Abstract

Bedaquiline is recommended by the World Health Organization for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). We pooled data from 5 cohorts of patients treated with bedaquiline in France, Georgia, Armenia, and South Africa and in a multicountry study. The rate of culture conversion to negative at 6 months (by the end of 6 months of treatment) was 78% (95% CI 73.5%–81.9%), and the treatment success rate was 65.8% (95% CI 59.9%–71.3%). Death rate was 11.7% (95% CI 7.0%–19.1%). Up to 91.1% (95% CI 82.2%–95.8%) of the patients experienced >1 adverse event, and 11.2% (95% CI 5.0%–23.2%) experienced a serious adverse event. Lung cavitations were consistently associated with unfavorable outcomes. The use of bedaquiline in MDR and XDR TB treatment regimens appears to be effective and safe across different settings, although the certainty of evidence was assessed as very low.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; MDR-TB; XDR-TB; Bedaquiline.

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The #microbiome and #tuberculosis: state of the art, potential applications, and defining the clinical research agenda (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda

Charissa C Naidoo, PhD, Georgina R Nyawo, MMedSc, Benjamin G Wu, MD, Prof Gerhard Walzl, PhD, Prof Robin M Warren, PhD, Leopoldo N Segal, MD, Grant Theron, PhD

Published: March 22, 2019 / DOI: https://doi.org/10.1016/S2213-2600(18)30501-0

 

Summary

The diverse microbial communities within our bodies produce metabolites that modulate host immune responses. Even the microbiome at distal sites has an important function in respiratory health. However, the clinical importance of the microbiome in tuberculosis, the biggest infectious cause of death worldwide, is only starting to be understood. Here, we critically review research on the microbiome’s association with pulmonary tuberculosis. The research indicates five main points: (1) susceptibility to infection and progression to active tuberculosis is altered by gut Helicobacter co-infection, (2) aerosol Mycobacterium tuberculosis infection changes the gut microbiota, (3) oral anaerobes in the lung make metabolites that decrease pulmonary immunity and predict progression, (4) the increased susceptibility to reinfection of patients who have previously been treated for tuberculosis is likely due to the depletion of T-cell epitopes on commensal gut non-tuberculosis mycobacteria, and (5) the prolonged antibiotic treatment required for cure of tuberculosis has long-term detrimental effects on the microbiome. We highlight knowledge gaps, considerations for addressing these knowledge gaps, and describe potential targets for modifying the microbiome to control tuberculosis.

Keywords: Tuberculosis; Microbiome.

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