The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

McGillivray, Amanda; Golden, Nadia; Kaushal, Deepak

doi:10.1074/jbc.m114.615534

Cited by 35 publications

(51 citation statements)

References 45 publications

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“…However, in vivo conditions such as granuloma, caseous necrosis tissue, or macrophages are hypoxic in nature [15–17]. If MTB resides in these tissues, the features of its biological metabolism might change [15–18], which may lead to variation in its resistance and growth characteristics. To identify whether the drug sensitivity and growth characteristics of MTB under hypoxic conditions are different from those under aerobic conditions, and to explore the related mechanisms, we conducted the following related research, using a large sample of MTB clinical isolates.…”

Section: Introductionmentioning

confidence: 99%

Impact of Hypoxia on Drug Resistance and Growth Characteristics of Mycobacterium tuberculosis Clinical Isolates

Gao

Yang

et al. 2016

PLoS ONE

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Mycobacterium tuberculosis (MTB) is a specific aerobic bacterium, but can survive under hypoxic conditions, such as those in lung cheese necrosis, granulomas, or macrophages. It is not clear whether the drug sensitivity and growth characteristics of MTB under hypoxic conditions are different from those under aerobic conditions. In this study, we examined the drug resistance and growth characteristics of MTB clinical isolates by a large sample of in vitro drug susceptibility tests, using an automatic growth instrument. Under hypoxic conditions, variance in drug resistance was observed in nearly one-third of the MTB strains and was defined as MTB strains with changed drug sensitivity (MTB-CDS). Among these strains, resistance in a considerable proportion of clinical strains was significantly increased, and some strains emerged as multi-drug resistant. Growth test results revealed a high growth rate and large survival number in macrophages under hypoxia in MTB-CDS. According to the results of fluorescence quantitative PCR, the expression of some genes, including RegX3 (involving RIF resistance), Rv0194 (efflux pump gene), four genes related to transcription regulation (KstR, DosR, Rv0081 and WhiB3) and gene related to translation regulation (DATIN), were upregulated significantly under hypoxic conditions compared to that under aerobic conditions (p < 0.05). Thus, we concluded that some MTB clinical isolates can survive under hypoxic conditions and their resistance could change. As for poor clinical outcomes in patients, based on routine drug susceptibility testing, drug susceptibility tests for tuberculosis under hypoxic conditions should also be recommended. However, the detailed mechanisms of the effect of hypoxia on drug sensitivity and growth characteristics of MTB clinical isolates still requires further study.

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Section: Introductionmentioning

confidence: 99%

Impact of Hypoxia on Drug Resistance and Growth Characteristics of Mycobacterium tuberculosis Clinical Isolates

Gao

Yang

et al. 2016

PLoS ONE

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“…We have previously reported that the ΔclgR mutant is compromised in growth when cultured in inducing stress conditions such as hypoxia or redox environment in vitro [7, 8]. In murine lungs and spleens, bacterial burdens of ΔclgR were not any lower than Mtb, in fact, at some time points significantly more ΔclgR bacilli could be isolated from murine tissues.…”

Section: Discussionmentioning

confidence: 99%

“…ClgR (Clp gene regulator) has been shown to be induced in response to stresses such as hypoxia, redox stress, and cell wall damages [3–8]. Proteolysis mechanisms regulated by ClgR are required for the resuscitation following the hypoxic shutdown of transcription activation mechanism and serve as a key phenomenon in the posttranscriptional regulation of gene expression in Mtb [9, 10].…”

Section: Introductionmentioning

confidence: 99%

“…Proteolysis mechanisms regulated by ClgR are required for the resuscitation following the hypoxic shutdown of transcription activation mechanism and serve as a key phenomenon in the posttranscriptional regulation of gene expression in Mtb [9, 10]. Our previous findings suggest that the isogenic ΔclgR mutant is susceptible for growth during hypoxic stresses in-vitro [8]. The Mtb encoded Clp protease system is essential for the degradation of potentially toxic unwanted proteins and prevents their accumulation in the cell [10–14].…”

Section: Introductionmentioning

confidence: 99%

“…As a result, Mtb experiences extensive damage to cellular proteins and their removal is crucial for the survival of the pathogen. The robust induction of clgR during hypoxia [7] clearly indicates that Clp gene regulator could also be critical within intragranolomatous environment where most bacilli persist and encounter host pressures such as hypoxia and redox stress [7, 8, 15–17]. However, we do not know what targets are proteolyzed during infection, and whether the spectrum of Clp targets is altered by stresses in-vivo.…”

Section: Introductionmentioning

confidence: 99%

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Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

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Tuberculosis (TB) is a leading cause of mortality and morbidity with an estimated 1.7 billion people latently infected with the pathogen worldwide. Clinically, TB infection presents itself as an asymptomatic infection, which gradually manifests to life threatening disease. The emergence of various drug resistant strains of Mycobacterium tuberculosis and lengthy duration of chemotherapy are major challenges in the field of TB drug development. Hence, there is an urgent need to develop scaffolds that possess a novel mechanism of action, can shorten the duration of therapy, and are active against both drug resistant and susceptible strains. In this review, we will discuss recent progress made in the field of TB drug development with emphasis on screening methods and drug targets from M. tuberculosis. The current review provides insights into mechanism of action of new scaffolds that are being evaluated in various stages of clinical trials. © 2018 IUBMB Life, 70(9):905-916, 2018.

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The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

Cited by 35 publications

References 45 publications

Impact of Hypoxia on Drug Resistance and Growth Characteristics of Mycobacterium tuberculosis Clinical Isolates

Impact of Hypoxia on Drug Resistance and Growth Characteristics of Mycobacterium tuberculosis Clinical Isolates

ClgR contributes to pulmonary pathology but not bacterial growth inMycobacterium tuberculosisinfection

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

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