Alternate efflux pump mechanism may contribute to drug resistance in extensively drug-resistant isolates of Mycobacterium tuberculosis

Kanji, Akbar; Hasan, Rumina; Zaver, Ambreen; Ali, Asho; Imtiaz, Kehkashan; Ashraf, Muhammad Waqar; Clark, Taane G.; McNerney, Ruth; Shafiq, Samreen; Hasan, Zahra

doi:10.1016/j.ijmyco.2016.09.064

Cited by 7 publications

(6 citation statements)

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“…Hence, detection of the mutation of gyrA gene could be used to predict OFX resistance in Chongqing. Notably, there were 13 OFX-resistant strains without mutation located in gyrA , indicating that there are other mechanisms related to OFX resistance, such as cell wall permeability and drug efflux pump [ 30 , 31 ]. On the other hand, there were 5 OFX-susceptible strains with mutation of gyrA gene, including one strain with an Gly88Ala mutation, two strains with Ala90Val mutation, and two strains with Asp94Ala mutation, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…This might limit the detection of the variety of gene mutations. Third, there was still some drug-resistant isolates that could not be explained in our study, such as mutations at other gene regions [ 35 ], permeability of cell membrane, and overexpression of drug efflux pump gene [ 30 , 31 ]. Therefore the other mechanisms of OFX resistance or KAN resistance will be detected in the further study and whole-genome sequencing might be needed to find more loci associated with drug resistance and to improve the performance of the sequencing-based assay.…”

Section: Discussionmentioning

confidence: 99%

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Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

et al. 2017

BioMed Research International

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This study aimed to investigate the prevalence of multidrug-resistant tuberculosis (MDR-TB) isolates resistant to the second-line antituberculosis drugs (SLDs) and its association with resistant-related gene mutations in Mycobacterium tuberculosis (M.tb) isolates from Southwest of China. There were 81 isolates resistant to at least one of the SLDs among 156 MDR-TB isolates (81/156, 51.9%). The rates of general resistance to each of the drugs were as follows: OFX (66/156, 42.3%), KAN (26/156, 16.7%), CAP (13/156, 8.3%), PTO (11/156, 7.1%), PAS (22/156, 14.1%), and AMK (20/156, 12.8%). Therefore, the most predominant pattern was resistant to OFX compared with other SLDs (P < 0.001). The results of sequencing showed that 80.2% OFX-resistant MDR-TB isolates contained gyrA mutation and 88.5% KAN-resistant isolates had rrs mutations with the most frequent mutation being A1401G. These results suggest that improper use of SLDs especially OFX is a real threat to effective MDR-TB treatment not only in China but also in the whole world. Furthermore the tuberculosis control agencies should carry out SLDs susceptibility testing and rapid screening in a broader population of TB patients immediately and the SLDs should be strictly regulated by the administration in order to maintain their efficacy to treat MDR-TB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

et al. 2017

BioMed Research International

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“…Recent studies showed drug resistance is usually caused by mutations, the inhA structural gene or the inha promoter region 5–7 , i.e ., resistance to INH caused by mutation of katG gene. Other studies showed that alternate efflux pump, which pumping drug out of cell, could be another cause of drug-resistance 8, 9 . However, these mechanisms could explain only part of all the M.tb drug-resistance.…”

Section: Introductionmentioning

confidence: 99%

Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide

Zhang

Jiang

et al. 2017

Sci Rep

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Tuberculosis is still on the top of infectious diseases list on both mobility and mortality, especially due to drug-resistance of Mycobacterium tuberculosis (M.tb). Ethionamide (ETH) is one of effective second line anti-TB drugs, a synthetic compound similar to isoniazid (INH) structurally, with existing severe problem of ETH resistance. ETH is a prodrug, which is activated by Etha inside M.tb, and etha is transcriptionally repressed by Ethr. We found that c-di-GMP could bind Ethr, enhanced the binding of Ethr to the promoter of etha, and then repressed the transcription of etha, thus caused resistance of M.tb to ETH. Through docking analysis and in vitro validation, we identified that c-di-GMP binds 3 amino acids of Ethr, i.e., Q125, R181 and E190, while the first 2 were the major binding sites. Homology analysis showed that Ethr was highly conservative among mycobacteria. Further docking analysis showed that c-di-GMP preferentially bound proteins of TetR family at the junction hole of symmetric dimer or tetramer proteins. Our results suggest a possible drug-resistance mechanism of ETH through the regulation of Ethr by c-di-GMP.

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“…However, there are still a few other mutations that can lead to resistance ( e.g. those that cause greater expression and/or activity of efflux pumps which remove the drug from within the tubercle bacillus) [ 17 ]. Over the next few years, mapping of DST with genetic mutations identified by whole-genome sequencing (WGS) will begin to define how the phenotypic and genotypic resistance relate to each other.…”

Section: Molecular Drug-resistance Testingmentioning

confidence: 99%

The Tuberculosis Network European Trials Group (TBNET): new directions in the management of tuberculosis

Bothamley

2017

Breathe

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The Tuberculosis Network European Trials Group (TBNET) is the largest clinical research organisation in Europe. Educational activities include the TBNET Academy and the European Advanced Course in Clinical Tuberculosis. Four of their publications are reviewed to show how the clinical management of tuberculosis is changing.Key pointsMost tuberculosis (TB) in contacts is found at their first visit.In contacts of pulmonary TB patients, the likelihood of later TB is ≤3%.Genetic tests can indicate when another antimycobacterial drug in the same class might be effective (e.g. rifabutin when there is rifampicin resistance or which injectable to choose).The short-course “Bangladesh” regimen can only be rarely used in Europe.Treatment completion in multidrug-resistant TB should not be included as a successful outcome.

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Alternate efflux pump mechanism may contribute to drug resistance in extensively drug-resistant isolates of Mycobacterium tuberculosis

Cited by 7 publications

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Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide

The Tuberculosis Network European Trials Group (TBNET): new directions in the management of tuberculosis

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