Drug Resistance Mechanisms in Mycobacterium tuberculosis

Palomino, Juan Carlos; Martin, Anandi

doi:10.3390/antibiotics3030317

Cited by 317 publications

(339 citation statements)

References 145 publications

(157 reference statements)

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“…Culture-based DST is limited by the low growth rate of M. tuberculosis and the poor reliability of results for pyrazinamide and ethambutol, drugs to which false resistance has been well documented (3)(4)(5)(6). Many specific mutations associated with drug resistance have been described (7)(8)(9)(10), and molecular assays targeting these mutations have improved the turnaround time (TAT) to detect resistance (11)(12)(13). However, these assays are limited to interrogating small portions of the genome (14), and strains of M. tuberculosis acquire resistance to drugs through various mechanisms, including chromosomal insertions, deletions, and single-nucleotide polymorphisms (SNPs).…”

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confidence: 99%

Comprehensive Whole-Genome Sequencing and Reporting of Drug Resistance Profiles on Clinical Cases of Mycobacterium tuberculosis in New York State

et al. 2017

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Whole-genome sequencing (WGS) is a newer alternative for tuberculosis (TB) diagnostics and is capable of providing rapid drug resistance profiles while performing species identification and capturing the data necessary for genotyping. Our laboratory developed and validated a comprehensive and sensitive WGS assay to characterize Mycobacterium tuberculosis and other M. tuberculosis complex (MTBC) strains, composed of a novel DNA extraction, optimized library preparation, pairedend WGS, and an in-house-developed bioinformatics pipeline. This new assay was assessed using 608 MTBC isolates, with 146 isolates during the validation portion of this study and 462 samples received prospectively. In February 2016, this assay was implemented to test all clinical cases of MTBC in New York State, including isolates and early positive Bactec mycobacterial growth indicator tube (MGIT) 960 cultures from primary specimens. Since the inception of the assay, we have assessed the accuracy of identification of MTBC strains to the species level, concordance with culture-based drug susceptibility testing (DST), and turnaround time. Species identification by WGS was determined to be 99% accurate. Concordance between drug resistance profiles generated by WGS and culture-based DST methods was 96% for eight drugs, with an average resistance-predictive value of 93% and susceptiblepredictive value of 96%. This single comprehensive WGS assay has replaced seven molecular assays and has resulted in resistance profiles being reported to physicians an average of 9 days sooner than with culture-based DST for first-line drugs and 32 days sooner for second-line drugs.

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confidence: 99%

Comprehensive Whole-Genome Sequencing and Reporting of Drug Resistance Profiles on Clinical Cases of Mycobacterium tuberculosis in New York State

et al. 2017

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“…Analysis of the inhA , katG and embB genes demonstrated classical mechanisms that have been associated with resistance to INH and EMB [5, 6]. No mutations were detected in the inhA gene or its promoter region in the isolates screened.…”

Section: Discussionmentioning

confidence: 99%

“…These include ropB (RIF), katG and inhA (INH), pncA (PZA) and embB (EMB). The clinical relevance of these mutations have been amply discussed [5, 6]. The recent application of whole genome sequencing has provided in-dept insight on the development and evolution of drug resistance, including the complexity of resistance in M.tuberculosis .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa

2016

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BackgroundIn South Africa, drug resistant tuberculosis is a major public health crisis in the face of the colossal HIV pandemic.MethodsIn an attempt to understand the distribution of drug resistance in our setting, we analysed the rpoB, katG, inhA, pncA and embB genes associated with resistance to key drugs used in the treatment of tuberculosis in clinical isolates of Mycobacterium tuberculosis in the KwaZulu-Natal province.ResultsClassical mutations were detected in the katG, inhA and embB genes associated with resistance to isoniazid and ethambutol. Diverse mutations were recorded in the multidrug resistant (MDR) and extensively drug resistant (XDR) isolates for the rpoB and pncA gene associated with resistance to rifampicin and pyrazinamide.Conclusions M.tuberculosis strains circulating in our setting display a combination of previously observed mutations, each mediating resistance to a different drug. The MDR and XDR TB isolates analysed in this study displayed classical mutations linked to INH and EMB resistance, whilst diverse mutations were linked to RIF and PZA resistance. The similarity of the XDR strains confirms reports of the clonality of the XDR epidemic. The successful dissemination of the drug resistant strains in the province underscores the need for rapid diagnostics to effectively diagnose drug resistance and guide treatment.

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“…The mechanisms by which M. tuberculosis is able to withstand the action of antibiotic therapy are highly diverse (23) and are largely defined by the genetic and epigenetic determinants of M. tuberculosis (24). Our study expands the drug resistance mechanisms exploited by M. tuberculosis and reveals a novel interaction at the interface of infection and consequent antimycobacterial drug exposure.…”

Section: Discussionmentioning

confidence: 99%

A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin

Bhagyaraj

Tiwari

Ahuja

et al. 2018

Journal of Biological Chemistry

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Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug efflux transporters in macrophages. This was evident from expression analysis of drug efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible M. tuberculosis, we observed increased intracellular survival of M. tuberculosis upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, M. tuberculosis infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters in vitro. We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of M. tuberculosis that arises from drug efflux systems of the host.M. tuberculosis is the primary causative agent of human TB and is responsible for maximum deaths than any other single http://www.jbc.org/cgi

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Drug Resistance Mechanisms in Mycobacterium tuberculosis

Cited by 317 publications

References 145 publications

Comprehensive Whole-Genome Sequencing and Reporting of Drug Resistance Profiles on Clinical Cases of Mycobacterium tuberculosis in New York State

Comprehensive Whole-Genome Sequencing and Reporting of Drug Resistance Profiles on Clinical Cases of Mycobacterium tuberculosis in New York State

Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa

A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin

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