Contribution of putative efflux pump genes to isoniazid resistance in clinical isolates of Mycobacterium tuberculosis

Narang, Asmita; Giri, Astha; Gupta, S. P.; Garima, Kushal; Bose, Mridula; Varma-Basil, Mandira

doi:10.4103/ijmy.ijmy_26_17

Cited by 31 publications

(13 citation statements)

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“…Contrary to our findings, Narang et al reported that Rv1250 and Rv876 were not overexpressed in any of the MDR isolates due to INH stress [9]. In this study, we revealed that among mono-resistant isolates, only were Rv1250 and Rv876 co-overexpressed in the PII-7 isolate in response to RIF.…”

Section: Discussioncontrasting

confidence: 99%

“…Other mechanisms of resistance, such as efflux pumps, act synergistically with the permeability barrier to reduce the passage of antimicrobials across the bacterial outer membrane [8]. Previous studies have demonstrated that the resistance of M. tuberculosis is associated with constitutive or inducible expression of efflux systems [9, 10]. Efflux pumps utilize the transmembrane electrochemical gradient of protons or sodium ions to extrude drugs from the cell, thereby neutralizing drug activity [11].…”

Section: Introductionmentioning

confidence: 99%

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Scrutinizing the drug resistance mechanism of multi- and extensively-drug resistant Mycobacterium tuberculosis: mutations versus efflux pumps

Ghajavand

Kamakoli

Khanipour

et al. 2019

Antimicrob Resist Infect Control

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Background In order to shorten the course of treatment and its effectiveness, it is essential to gain an in-depth insight into the drug resistance mechanisms of Mycobacterium tuberculosis ( M. tuberculosis ). Methods In this study, we evaluated the contribution of 26 drug efflux pumps plus target gene mutations to the drug resistance levels in multi-drug resistant (MDR)/pre-extensively drug-resistant (pre-XDR)/extensively drug-resistant (XDR) and mono-drug resistant clinical isolates of M. tuberculosis . The panels of 25 M. tuberculosis clinical strains were characterized for drug resistance-associated mutations with whole-genome sequencing and antibiotic profiles in the presence and absence of efflux inhibitor verapamil (VP). Results Different MICs were observed for the same target gene mutations. Out of the 16 MDR/pre-XDR/XDR isolates, 6 (37.5%) and 3 (18.8%) isolates demonstrated a significant decrease in rifampicin (RIF) MIC and isoniazid (INH) MIC due to the VP exposure (64 μg/mL), respectively. Susceptibility to RIF was fully restored in two isolates after VP exposure. Moreover, the efflux pump genes of Rv2938, Rv2936, Rv1145, Rv1146, Rv933, Rv1250, Rv876 , Rv2333, Rv2459, Rv849, and Rv1819 were overexpressed in the presence of anti-TB drugs, showing the contribution of these efflux pumps to the overall resistance phenotype. Conclusions Our results clearly showed that efflux systems, besides spontaneous mutations, play a role in the development of INH/RIF resistance. In addition, although VP was effective in reducing the expression of some efflux pumps, it was not very successful at the phenotypic level. Electronic supplementary material The online version of this article (10.1186/s13756-019-0516-4) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scrutinizing the drug resistance mechanism of multi- and extensively-drug resistant Mycobacterium tuberculosis: mutations versus efflux pumps

Ghajavand

Kamakoli

Khanipour

et al. 2019

Antimicrob Resist Infect Control

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“…The other genes do not appear to have any link with the biosynthesis of these fatty acids, but may be induced because of the toxic effects of isoniazid. Moreover, upregulation of the expression of the gene efpA , which encodes a major facilitator superfamily (MFS) efflux pump, as well as the upregulation of iniA , which encodes putative pump component, could participate in intrinsic resistance to isoniazid, as has been reported in other studies (Colangeli et al, 2005; Gupta et al, 2010; Li et al, 2015; Narang et al, 2017). iniA is upregulated along with iniB and iniC , these genes are indeed organized in operon under the control of iniBAC promoter and upregulated by various cell envelope inhibitor (Alland et al, 1998, 2000).…”

Section: Isoniazid Induced Changes In Gene Expressionmentioning

confidence: 53%

Genome-Wide Transcriptional Responses of Mycobacterium to Antibiotics

2019

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Antibiotics can stimulate or depress gene expression in bacteria. The analysis of transcriptional responses of Mycobacterium to antimycobacterial compounds has improved our understanding of the mode of action of various drug classes and the efficacy and effect of such compounds on the global metabolism of Mycobacterium . This approach can provide new insights for known antibiotics, for example those currently used for tuberculosis treatment, as well as help to identify the mode of action and predict the targets of new compounds identified by whole-cell screening assays. In addition, changes in gene expression profiles after antimycobacterial treatment can provide information about the adaptive ability of bacteria to escape the effects of antibiotics and allow monitoring of the physiology of the bacteria during treatment. Genome-wide expression profiling also makes it possible to pinpoint genes differentially expressed between drug sensitive Mycobacterium and multidrug-resistant clinical isolates. Finally, genes involved in adaptive responses and drug tolerance could become new targets for improving the efficacy of existing antibiotics.

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“…Major facilitator superfamily (MFS) [40] Isoniazid Rv1272c-1273c ATP-binding transport protein family (ABC transporters) [33] Isoniazid, tetracycline, rifampicin and clofazimine Rv1410c (p55) Major facilitator superfamily (MFS) [33,37] Isoniazid, Rifampicin, Ethambutol, Streptomycin Rv1458c, Rv1457c, Rv1456c…”

Section: Rv1258cmentioning

confidence: 99%

Efflux pump genes variants in MDR TB strains with discrepant phenotype-genotype correlations may further guide drug resistance interpretation

Hasan¹,

Razzak²,

Kanji³

et al. 2023

Preprint

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Introduction: Whole genome analysis of Mycobacterium tuberculosis (MTB) is an increasingly important method of identification of multi-drug resistance (MDR) in clinical isolates. It is based on the identification of single nucleotide variants (SNVs) in genes associated with resistance. However, there remain gaps in our understanding of phenotype – genotype correlation between strains. Efflux pumps contribute to drug resistance and here we studied SNVs in key efflux pump genes (EP) to investigate their association with resistance. Methods: Whole genome data of 2221 MTB isolates comprising 1432 susceptible and 789 drug resistant strains were downloaded from ReSeqTB database. MTB lineage and resistance genotyping analysis was performed using an in-house bioinformatics pipeline, MTB-VCF. SNVs in 47 EP genes were categorized according to their SIFT/Polyphen scores. Results: We identified variants unique to EP in DR isolates. SIFT/Polyphen effect analysis determined 38 high impact SNVs across twenty EP genes (EP) to be present in these 789 genomes. SNVs were not associated with MTB lineages. The EPs with SNVs in DR isolates were Rv1819, Rv0194, Rv0507, Rv2333c, Rv3728, Rv3823, Rv1250, Rv1273, Rv1458, Rv1634, Rv1217, Rv1218, Rv0450, Rv0676c, Rv0191, Rv3008, Rv3756, Rv2688, Rv1704 and Rv1877. Examination of 52 isolates with discrepant phenotype-genotypes resistance comprising, MDR, pre-XDR and XDR strains revealed SNVs in EP associated with RIF and INH (Rv0194, Rv1217_1218, Rv1819, Rv0450, Rv1458, Rv0507), and those associated with fluoroquinolone (Rv1634 and Rv2688) resistance. Conclusions: We identified SNVs in efflux pumps which could contribute to resistance in MTB strains. It may be important to consider these as part of MTB genome-based resistance interpretation. Functional studies combined with GWAS and RNA profiling would further confirm these findings.

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Contribution of putative efflux pump genes to isoniazid resistance in clinical isolates of Mycobacterium tuberculosis

Abstract: The high number of efflux genes overexpressed in an INH-resistant isolate with no known INH resistance associated mutations, suggests a role for efflux pumps in resistance to this antituberculous agent, with the role of Rv0194 and Rv0507 in INH resistance being reported for the first time.

Cited by 31 publications

References 1 publication

Scrutinizing the drug resistance mechanism of multi- and extensively-drug resistant Mycobacterium tuberculosis: mutations versus efflux pumps

Scrutinizing the drug resistance mechanism of multi- and extensively-drug resistant Mycobacterium tuberculosis: mutations versus efflux pumps

Genome-Wide Transcriptional Responses of Mycobacterium to Antibiotics

Efflux pump genes variants in MDR TB strains with discrepant phenotype-genotype correlations may further guide drug resistance interpretation

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