#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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#Isoniazid (INH) mono- #resistance and #tuberculosis (TB) #treatment success: analysis of #European #surveillance data, 2002 to 2014 (Euro Surveill., abstract)

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

Isoniazid (INH) mono-resistance and tuberculosis (TB) treatment success: analysis of European surveillance data, 2002 to 2014

Basel Karo1,2,3,4, Anke Kohlenberg4,5, Vahur Hollo5, Raquel Duarte6, Lena Fiebig33,7, Sarah Jackson8, Cathriona Kearns9, Csaba Ködmön5, Maria Korzeniewska-Kosela 10, Dimitrios Papaventsis11, Ivan Solovic12, Dick van Soolingen13, Marieke J. van der Werf5

Affiliations: 1 EPIET: European Programme of Intervention Epidemiology Training, European Centre for Disease Prevention and Control, Stockholm, Sweden; 2 Field Epidemiology South East & London, National infection Service, Public Health England, London, United Kingdom; 3 Infectious Disease Department, Robert Koch Institute, Berlin, Germany; 4 These authors contributed equally to this article and share first authorship; 5 European Centre for Disease Prevention and Control, Stockholm, Sweden; 6 Directorate General of Health, Lisbon, Portugal; 7 Apopo, Sokoine University of Agriculture, Morogoro, Tanzania; 8 Health Protection Surveillance Centre, Dublin, Ireland; 9 Public Health Agency, Belfast, Northern Ireland; 10 National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland; 11 National Reference Laboratory for Mycobacteria, ‘Sotiria’ Chest Diseases Hospital, Athens, Greece; 12 National Institute for TB, Lung Diseases and Thoracic Surgery, Vysne Hagy, Catholic University Ruzomberok, Ruzomberok, Slovakia; 13 Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, Bilthoven, The Netherlands

Correspondence: Anke Kohlenberganke.kohlenbergecdc.europa.eu

Citation style for this article: Karo Basel, Kohlenberg Anke, Hollo Vahur, Duarte Raquel, Fiebig3 Lena, Jackson Sarah, Kearns Cathriona, Ködmön Csaba, Korzeniewska-Kosela Maria, Papaventsis Dimitrios, Solovic Ivan, van Soolingen Dick, van der Werf Marieke J.. Isoniazid (INH) mono-resistance and tuberculosis (TB) treatment success: analysis of European surveillance data, 2002 to 2014. Euro Surveill. 2019;24(12):pii=1800392. https://doi.org/10.2807/1560-7917.ES.2019.24.12.1800392

Received: 17 Jul 2018;   Accepted: 09 Feb 2019

 

Abstract

Introduction:

Isoniazid (INH) is an essential drug for tuberculosis (TB) treatment. Resistance to INH may increase the likelihood of negative treatment outcome.

Aim:

We aimed to determine the impact of INH mono-resistance on TB treatment outcome in the European Union/European Economic Area and to identify risk factors for unsuccessful outcome in cases with INH mono-resistant TB.

Methods:

In this observational study, we retrospectively analysed TB cases that were diagnosed in 2002–14 and included in the European Surveillance System (TESSy). Multilevel logistic regression models were applied to identify risk factors and correct for clustering of cases within countries.

Results:

A total of 187,370 susceptible and 7,578 INH mono-resistant TB cases from 24 countries were included in the outcome analysis. Treatment was successful in 74.0% of INH mono-resistant and 77.4% of susceptible TB cases. In the final model, treatment success was lower among INH mono-resistant cases (Odds ratio (OR): 0.7; 95% confidence interval (CI): 0.6–0.9; adjusted absolute difference in treatment success: 5.3%). Among INH mono-resistant TB cases, unsuccessful treatment outcome was associated with age above median (OR: 1.3; 95% CI: 1.2–1.5), male sex (OR: 1.3; 95% CI: 1.1–1.4), positive smear microscopy (OR: 1.3; 95% CI: 1.1–1.4), positive HIV status (OR: 3.3; 95% CI: 1.6–6.5) and a prior TB history (OR: 1.8; 95% CI: 1.5–2.2).

Conclusions:

This study provides evidence for an association between INH mono-resistance and a lower likelihood of TB treatment success. Increased attention should be paid to timely detection and management of INH mono-resistant TB.

© This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; European Region; Isoniazid.

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#Prevalence of drug- #resistant #tuberculosis and imputed burden in #SouthAfrica: a national and sub-national cross-sectional survey (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a national and sub-national cross-sectional survey

Nazir Ahmed Ismail, FCPath, Lindiwe Mvusi, MBChB, Ananta Nanoo, MSc, Andries Dreyer, FCPath, Shaheed V Omar, PhD, Sanni Babatunde, PhD, Thabo Molebatsi, MPH, Martie van der Walt, PhD, Adeboye Adelekan, PhD, Varough Deyde, PhD, Chikwe Ihekweazu, FFPH†, Prof Shabir A Madhi, PhD†

† Contributed equally

Published: 20 April 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30222-6

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001–02 estimates.

Methods

A cross-sectional survey was done between June 15, 2012–June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, inverse probability weighted against routine data, and estimates were derived using a random effects model.

Findings

101 422 participants were tested in 2012–14. Nationally, the prevalence of MDR tuberculosis was 2·1% (95% CI 1·5–2·7) among new tuberculosis cases and 4·6% (3·2–6·0) among retreatment cases. The provincial point prevalence of MDR tuberculosis ranged between 1·6% (95% CI 0·9–2·9) and 5·1% (3·7–7·0). Overall, the prevalence of rifampicin-resistant tuberculosis (4·6%, 95% CI 3·5–5·7) was higher than the prevalence of MDR tuberculosis (2·8%, 2·0–3·6; p=0·01). Comparing the current survey with the previous (2001–02) survey, the overall MDR tuberculosis prevalence was 2·8% versus 2·9% and prevalance of rifampicin-resistant tuberculosis was 3·4% versus 1·8%, respectively. The prevalence of isoniazid mono-resistant tuberculosis was above 5% in all provinces. The prevalence of ethionamide and pyrazinamide resistance among MDR tuberculosis cases was 44·7% (95% CI 25·9–63·6) and 59·1% (49·0–69·1), respectively. The prevalence of XDR tuberculosis was 4·9% (95% CI 1·0–8·8). Nationally, the estimated numbers of cases of rifampicin-resistant tuberculosis, MDR tuberculosis, and isoniazid mono-resistant tuberculosis for 2014 were 13 551, 8249, and 17 970, respectively.

Interpretation

The overall prevalence of MDR tuberculosis in South Africa in 2012–14 was similar to that in 2001–02; however, prevalence of rifampicin-resistant tuberculosis almost doubled among new cases. Furthermore, the high prevalence of isoniazid mono-resistant tuberculosis, not routinely screened for, and resistance to second-line drugs has implications for empirical management.

Funding

President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention under the terms of 1U19GH000571.

Keywords: South Africa; Tuberculosis; Antibiotics; Drugs Resistance; MDR-TB; Rifampicin; Isoniazid.

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Increasing Prevalence of #Rifampicin-Resistant Mycobacterium #tuberculosis is Associated with the Transmission of Strains Harboring Compensatory Mutations in #China: A 10-year Comparative Analysis (AAC, abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Increasing Prevalence of Rifampicin-Resistant Mycobacterium tuberculosis is Associated with the Transmission of Strains Harboring Compensatory Mutations in China: A 10-year Comparative Analysis

Fengmin Huo1,  Jingjing Luo1,  Jin Shi2,  Zhaojing Zong1,  Wei Jing1, Wenzhu Dong1,  Lingling Dong1,  Yifeng Ma1,  Qian Liang1,  Yuanyuan Shang1, Hairong Huang1* and Yu Pang1*

Author Affiliations: 1 National Clinical Laboratory on Tuberculosis, Beijing Key laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China; 2 Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China

 

ABSTRACT

In this report, we conducted bacterial population profile studies to assess trends of rifampicin (RIF) resistance from 2005 to 2015 of Mycobacterium tuberculosis (MTB) isolates collected across China. A total of randomly selected 273 and 269 MTB isolates from 2005 and 2015, respectively, were analyzed. The rates of RIF resistance (36.4%), isoniazid resistance (39.0%), and levofloxacin resistance (25.7%) in 2015 were significantly higher than in 2005 (28.2%, 30.0%, and 15.4%, respectively; P < 0.05). Genotypic data revealed 256 (95.2%) Beijing-type isolates in 2015, a rate significantly higher than that of 2005 (86.4%) (P < 0.01). A higher proportion of mutations were identified within the rifampin resistance determining region (RRDR) of rpoB in isolates from 2015 (99.0%) than in 2005 isolates (85.7%, P< 0.01). In addition, a significantly higher proportion of RIF-resistant isolates carrying compensatory mutations were observed in 2015 (31.6%) than in 2005 (7.8%). Notably, the great majority of these compensatory mutations (91.9%) were observed in isolates that harbored a mutation of codon 531 of the rpoB gene. In conclusion, our data demonstrate that resistance to RIF, isoniazid, and levofloxacin has become significantly more prevalent during the past decade. In addition, the prevalence of the Beijing genotype significantly increased from 2005 to 2015. Notably, a significantly increased frequency of strains with mutations in rpoC or rpoA is observed in those that have codon 531 mutations suggests that they may be compensatory, and may play a role in facilitating transmission.

 

FOOTNOTES

*Corresponding author. Mailing address for Yu Pang: Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, China. Phone: 86 10 8950 9359. Fax: 86 10 8950 9359. E-mail: pangyupound@163.com.

*Mailing address for Hairong Huang: Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, China. Phone: 86 10 8950 9359. Fax: 86 10 8950 9359. E-mail: huanghairong@tb123.org.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; China; Rifampicin.

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#Vitamin C potentiates the killing of #Mycobacterium tuberculosis by the first-line #tuberculosis drugs #isoniazid and #rifampicin in mice (J Antimicrob Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Vitamin C potentiates the killing of Mycobacterium tuberculosis by the first-line tuberculosis drugs isoniazid and rifampicin in mice

Catherine Vilchèze,  John Kim and  William R. Jacobs Jr*

Author Affiliations: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

 

ABSTRACT

The treatment of drug-susceptible tuberculosis (TB) is long and cumbersome. Mismanagement of TB treatment can lead to the emergence of drug resistance in patients, so shortening the treatment duration could significantly improve TB chemotherapy and prevent the development of drug resistance. We had previously discovered that high concentrations of vitamin C sterilize cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis. Here, we tested sub-inhibitory concentration of vitamin C in combination with TB drugs against M. tuberculosis in vitro and in a mouse model of M. tuberculosis infection. In vivo, we showed that vitamin C level in mouse serum can be increased by intraperitoneal injection of vitamin C to reach vitamin C levels close to the concentrations required for activity in vitro. Although vitamin C had no activity by itself in M. tuberculosis-infected mice, the combination of vitamin C with the first-line TB drugs isoniazid and rifampicin reduced the bacterial burden in the lungs of M. tuberculosis-infected mice faster than isoniazid and rifampicin combined in two independent experiments. These experiments suggest that the addition of vitamin C to first-line TB drugs could shorten TB treatment. Vitamin C, an inexpensive and non-toxic compound, could be easily added to the TB pharmacopeia to substantially improve chemotherapy outcome, which would have a significant impact on the worldwide TB community.

 

FOOTNOTES

*Corresponding author. Tel: (718) 678-1075; Fax: (718) 678-1085; E-mail: jacobsw@hhmi.org

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Tuberculosis; Antibiotics; Vitamic C; Isoniazid; Rifampicin.

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