scholarly journals A chemical-genetic map of the pathways controlling drug potency in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Shuqi Li ◽  
Nicholas C Poulton ◽  
Jesseon S Chang ◽  
Zachary A Azadian ◽  
Michael A Dejusus ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genetic Map ◽  
Drug Efficacy ◽  
Multidrug Resistant ◽  
Loss Of Function ◽  
Intrinsic Resistance ◽  
Acquired Drug Resistance ◽  
Chemical Genetic ◽  
Resistant Tuberculosis

Mycobacterium tuberculosis infection is notoriously difficult to treat. To define the bacterial determinants that limit treatment efficacy, we developed a CRISPRi chemical genetics platform to titrate the expression of nearly all Mtb genes and quantify bacterial fitness in the presence of different drugs. Mining this dataset, we discovered diverse mechanisms of intrinsic drug resistance, unveiling hundreds of potential targets for synergistic drug combinations. Combining our data with comparative genomics of Mtb clinical isolates, we further identified new mechanisms of acquired drug resistance, one of which is associated with the emergence of a multidrug-resistant tuberculosis (TB) outbreak in South America. Lastly, we make the unexpected discovery of loss-of-function mutations in the intrinsic resistance factor whiB7 in an entire Mtb sublineage endemic to Southeast Asia, presenting an opportunity to repurpose macrolides to treat TB. This chemical-genetic map provides a rich resource to understand drug efficacy and guide future TB drug development and treatment.

scholarly journals Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis

2007 ◽  
Vol 51 (7) ◽  
pp. 2618-2620 ◽  
Author(s):  
Xin Shen ◽  
Guo-miao Shen ◽  
Jie Wu ◽  
Xiao-hong Gui ◽  
Xia Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Odds Ratio ◽  
Rapid Detection ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Candidate Marker ◽  
Resistant Tuberculosis

ABSTRACT embB306 mutants were detected in both ethambutol (EMB)-resistant and EMB-susceptible strains of Mycobacterium tuberculosis. Multidrug-resistant (MDR) strains had a higher proportion of embB306 mutants than non-MDR strains (odds ratio, 6.78; P < 0.001). The embB306 locus is a candidate marker for rapid detection of MDR and extremely drug resistant tuberculosis.

scholarly journals Mutations inpepQConfer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis

2016 ◽  
Vol 60 (8) ◽  
pp. 4590-4599 ◽  
Author(s):  
Deepak Almeida ◽  
Thomas Ioerger ◽  
Sandeep Tyagi ◽  
Si-Yang Li ◽  
Khisimuzi Mdluli ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Loss Of Function ◽  
Content Type ◽  
Low Level ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

ABSTRACTThe novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations inRv0678that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and clofazimine cross-resistance inMycobacterium tuberculosis: loss-of-function mutations inpepQ(Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase.pepQmutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without clofazimine, and were shown to have bedaquiline and clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression ofRv0678,mmpS5, ormmpL5between mutant and parent strains. Complementation of apepQmutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility bothin vitroand in mice. Although the mechanism by which mutations inpepQconfer bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.

scholarly journals A computational perspective on the dynamic behaviour of recurrent drug resistance mutations in the pncA gene from Mycobacterium tuberculosis

RSC Advances ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 2476-2486
Author(s):  
Taimoor Khan ◽  
Abbas Khan ◽  
Syed Shujait Ali ◽  
Shahid Ali ◽  
Dong-Qing Wei
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Causes Of Death ◽  
Dynamic Behaviour ◽  
Multidrug Resistant ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Computational Perspective

Tuberculosis is still one of the top 10 causes of death worldwide, particularly with the emergence of multidrug-resistant tuberculosis.

Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey, Mexico

2004 ◽  
Vol 53 (2) ◽  
pp. 107-113 ◽  
Author(s):  
Srinivas V. Ramaswamy ◽  
Shu-Jun Dou ◽  
Adrian Rendon ◽  
Zhenhua Yang ◽  
M. Donald Cave ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Secondary Resistance ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Genotypic Analysis ◽  
Mdr Tb

Thirty-seven multidrug-resistant and 13 pan-susceptible isolates of Mycobacterium tuberculosis were analysed for the diversity of genotypes associated with known drug-resistance mechanisms. The isolates were obtained from patients attending a university tuberculosis clinic in Monterrey, Mexico. A total of 25 IS6110-RFLP patterns were obtained from the multidrug-resistant tuberculosis (MDR-TB) isolates. Approximately 65 % of the MDR-TB isolates were attributed to secondary resistance. Different drug-susceptibility patterns were seen with the clustered isolates. The percentage of isolates resistant to isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STR) was 100, 97.3, 48.7 and 67.6, respectively. The most common resistance-associated polymorphisms for the four drugs were as follows: INH, Ser315Thr (67.6 %) in katG; RIF, Ser450Leu (41.7 %) in rpoB; EMB, Met306Ile/Val/Leu (66.7 %) in embB; and STR, Lys43Arg (24 %) in rpsL. Drug-resistance-associated mutations were similar to changes occurring in isolates from other areas of the world, but unique, previously unreported, mutations in katG (n = 5), rpoB (n = 1) and rrs (n = 3) were also identified.

scholarly journals Acquired Drug Resistance inMycobacterium tuberculosisand Poor Outcomes among Patients with Multidrug-Resistant Tuberculosis

2015 ◽  
Vol 21 (6) ◽  
pp. 992-1001 ◽  
Author(s):  
Russell R. Kempker ◽  
Maia Kipiani ◽  
Veriko Mirtskhulava ◽  
Nestani Tukvadze ◽  
Matthew J. Magee ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistant ◽  
Acquired Drug Resistance ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Poor Outcomes

scholarly journals Analysis of drug resistance and mutation profiles in Mycobacterium tuberculosis isolates in a surveillance site in Beijing, China

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098493
Author(s):  
Jie Zhang ◽  
Yixuan Ren ◽  
Liping Pan ◽  
Junli Yi ◽  
Tong Guan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Testing ◽  
Multidrug Resistant ◽  
High Rate ◽  
Drug Resistant ◽  
Surveillance Site ◽  
Mdr Tb ◽  
Previously Treated Patients ◽  
Beijing China

Objective This study analyzed drug resistance and mutations profiles in Mycobacterium tuberculosis isolates in a surveillance site in Huairou District, Beijing, China. Methods The proportion method was used to assess drug resistance profiles for four first-line and seven second-line anti-tuberculosis (TB) drugs. Molecular line probe assays were used for the rapid detection of resistance to rifampicin (RIF) and isoniazid (INH). Results Among 235 strains of M. tuberculosis, 79 (33.6%) isolates were resistant to one or more drugs. The isolates included 18 monoresistant (7.7%), 19 polyresistant (8.1%), 28 RIF-resistant (11.9%), 24 multidrug-resistant (MDR) (10.2%), 7 pre-extensively drug-resistant (XDR, 3.0%), and 2 XDR strains (0.9%). A higher rate of MDR-TB was detected among previously treated patients than among patients with newly diagnosed TB (34.5% vs. 6.8%). The majority (62.5%) of RIF-resistant isolates exhibited a mutation at S531L in the DNA-dependent RNA polymerase gene. Meanwhile, 62.9% of INH-resistant isolates carried a mutation at S315T1 in the katG gene. Conclusion Our results confirmed the high rate of drug-resistant TB, especially MDR-TB, in Huairou District, Beijing, China. Therefore, detailed drug testing is crucial in the evaluation of MDR-TB treatment.

Emergence of Extensive Drug Resistance during Treatment for Multidrug-Resistant Tuberculosis

2008 ◽  
Vol 359 (22) ◽  
pp. 2398-2400 ◽  
Author(s):  
Helen S. Cox ◽  
Caterina Sibilia ◽  
Silke Feuerriegel ◽  
Stobdan Kalon ◽  
Jonny Polonsky ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistant ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Extensive Drug Resistance
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