Variants of katG, inhA and nat genes are not associated with mutations in efflux pump genes (mmpL3 and mmpL7) in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from India

Unissa, Ameeruddin Nusrath; Dusthackeer, V.N. Azger; Kumar, Micheal Prem; Nagarajan, P.; Sukumar, Swathi; Kumari, V. Indira; Lakshmi, Appisetty Ramya; Hanna, Luke Elizabeth

doi:10.1016/j.tube.2017.07.014

Cited by 8 publications

(2 citation statements)

References 16 publications

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“…Moreover, the ferric uptake regulator gene ( furA ) and several efflux protein-encoding genes ( iniABC and efpA ) have been shown to be mutated in INH-resistant M. tuberculosis isolates 9 – 12 . Investigators have also studied other efflux (mmpL family) genes and their significance in INH resistance 13 . Additionally, mutations in trehalose dimycolyl transferase ( fbpC ), a regulatory gene governing the expression of a polyketide synthase ( srmR ), as well as in Rv0340 , Rv1592c, Rv1772 , fadE24 , ndh , and nat have been identified in resistant M. tuberculosis strains 14 – 17 .…”

Section: Introductionmentioning

confidence: 99%

The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non-315 in multidrug-resistant tuberculosis isolates from China

Liu

Jiang

Zhao

et al. 2018

Emerging Microbes & Infections

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Whole-genome sequencing was used to analyze the profiles of isoniazid (INH) resistance-related mutations among 188 multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) and mono-INH-resistant isolates collected in a recent Chinese national survey. Mutations were detected in 18 structural genes and two promoter regions in 96.8% of 188 resistant isolates. There were high mutation frequencies in katG, the inhA promoter, and ahpC-oxyR regulator regions in INH-resistant isolates with frequencies of 86.2%, 19.6%, and 18.6%, respectively. Moreover, a high diversity of mutations was identified as 102 mutants contained various types of single or combined gene mutations in the INH-resistant group of isolates. The cumulative frequencies of katG 315 or inhA-P/inhA mutations was 68.1% (128/188) for the INH-resistant isolates. Of these isolates, 46 isolates (24.5% of 188) exhibited a high level of resistance. A high level of resistance was also observed in 21 isolates (11.2% of 188) with single ahpC-oxyR mutations or a combination of ahpC-oxyR and katG non-315 mutations. The remaining 17 mutations occurred sporadically and emerged in isolates with combined katG mutations. Such development of INH resistance is likely due to an accumulation of mutations under the pressure of drug selection. Thus, these findings provided insights on the levels of INH resistance and its correlation with the combinatorial mutation effect resulting from less frequent genes (inhA and/or ahpC). Such knowledge of other genes (apart from katG) in high-level resistance will aid in developing better strategies for the diagnosis and management of TB.

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Section: Introductionmentioning

confidence: 99%

The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non-315 in multidrug-resistant tuberculosis isolates from China

Liu

Jiang

Zhao

et al. 2018

Emerging Microbes & Infections

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“…pst B, is involved in the efflux of isoniazid and rifampicin in M. tuberculosis and M. smegmatis. 23 Efflux pump mmpL3 is involved in isoniazid resistance in M. tuberculosis . 21, 24 Disruption of mmpL11 in M.tb leads to attenuation of growth in mice lungs 25 and delayed heme uptake.…”

Section: Resultsmentioning

confidence: 99%

Laboratory evolution ofMycobacterium smegmatisin the presence of a fluoroquinolone leads to extreme drug resistance phenotype through the over-expression ofMsmeg_5659-61 efflux pump.

Rai

Padwal

Purkayastha

et al. 2022

Preprint

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Resistance to multiple drugs is one of the significant barriers in the treatment of tuberculosis (TB). Knowledge of mechanisms of resistance is important to design effective treatment strategies. While mutations in genes coding for drug targets are thought to be the primary source of drug resistance, absence of mutations in these genes in many clinical strains suggests additional mechanisms of resistance. In this study, we employ adaptive laboratory evolution of Mycobacterium smegmatis to understand alternate mechanisms of drug resistance to norfloxacin, a fluoroquinolone (FQ). Results show that, in addition to fluoroquinolones, the evolved strain, Norr, is resistant to first-line drugs, rifampicin and isoniazid, and a second-line drug (amikacin), exhibiting extreme drug resistance phenotype. However, mutations were absent in any of the drug target genes. Drug uptake studies revealed that resistance is an attribute of decreased intracellular accumulation, primarily due to increased efflux. Further, drug transport kinetics demonstrate the involvement of efflux mediated resistance, which was found to be reversed in the presence of efflux pump inhibitors (EPIs). Gene transcript analysis suggests differential upregulation of multiple efflux pumps across the genome of the mutant. Overexpression of one of the upregulated efflux pumps Msmeg_5659-5661, partially explains the XDR phenotype of the mutant, while also suggesting that the contribution of other efflux pumps is significant. Whole-genome sequencing (WGS) of Norr reveals that a mutation in soxR, a transcriptional regulator, could be responsible for the upregulation of the Msmeg_5659-5661 efflux pump by direct regulation, and other efflux pumps via indirect regulation. Thus, the present work demonstrates that high resistance to multiple drugs can arise even when the Mycobacterium was subjected to a single selection pressure. Further, alterations in drug transport is an important mechanism that leads to resistance to multiple drugs simultaneously.

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Altered drug efflux under iron deprivation unveils abrogated MmpL3 driven mycolic acid transport and fluidity in mycobacteria

2018

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Variants of katG, inhA and nat genes are not associated with mutations in efflux pump genes (mmpL3 and mmpL7) in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from India

Cited by 8 publications

References 16 publications

The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non-315 in multidrug-resistant tuberculosis isolates from China

The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non-315 in multidrug-resistant tuberculosis isolates from China

Laboratory evolution ofMycobacterium smegmatisin the presence of a fluoroquinolone leads to extreme drug resistance phenotype through the over-expression ofMsmeg_5659-61 efflux pump.

Altered drug efflux under iron deprivation unveils abrogated MmpL3 driven mycolic acid transport and fluidity in mycobacteria

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