Deficiency of GntR Family Regulator MSMEG_5174 Promotes Mycobacterium smegmatis Resistance to Aminoglycosides via Manipulating Purine Metabolism

Deng, Wanyan; Zheng, Zengzhang; Chen, Yi; Yang, Maoyi; Yan, Jun; Li, Wu; Zeng, Jie; Xie, Jianping; Gong, Sitang; Zeng, Huasong

doi:10.3389/fmicb.2022.919538

Cited by 3 publications

(2 citation statements)

References 46 publications

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“…These mutations mapping in the rv2747 (argA) and rv1655 (argD) genes were associated with increased survival during RIF exposure, as well as with minimum inhibitory concentration (MIC) increase to clarithromycin, again related to the up-regulation of whiB7. Modern Beijing isolates and one phylogenetically intermediate Beijing isolate harbored a loss-of-function mutation in tap; thus Rv0324 Deletion Hypersensitivity to BDQ (Peterson et al, 2016) Rv0678 (Mutated) Inactivation mmpS5-mmpL5 operon Resistance to BDQ and CFZ (Kadura et al, 2020) Rv0880 Deletion Hypersensitivity to BDQ (Peterson et al, 2016) Rv1152 (Observed) overexpression Resistance to VAN (Zeng et al, 2016;Deng et al, 2022) Rv3082c (Mutated) overexpression mymA operon (Rv3083 to Rv3089)…”

Section: Whib Family (Whib1-7)mentioning

confidence: 99%

“…Rv1152 is involved in the regulation of cell wall permeability (Zeng et al, 2016;Deng et al, 2022). This transcriptional regulator is involved in acid and cell surface stress response and plays an important role in determining VAN resistance by negatively regulating genes responsive to this glycopeptide antibiotic.…”

Section: Gntr Family Transcriptional Regulatorsmentioning

confidence: 99%

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Transcriptional regulation and drug resistance in Mycobacterium tuberculosis

Miotto

Sorrentino

Giorgi

et al. 2022

Front. Cell. Infect. Microbiol.

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Bacterial drug resistance is one of the major challenges to present and future human health, as the continuous selection of multidrug resistant bacteria poses at serious risk the possibility to treat infectious diseases in the near future. One of the infection at higher risk to become incurable is tuberculosis, due to the few drugs available in the market against Mycobacterium tuberculosis. Drug resistance in this species is usually due to point mutations in the drug target or in proteins required to activate prodrugs. However, another interesting and underexplored aspect of bacterial physiology with important impact on drug susceptibility is represented by the changes in transcriptional regulation following drug exposure. The main regulators involved in this phenomenon in M. tuberculosis are the sigma factors, and regulators belonging to the WhiB, GntR, XRE, Mar and TetR families. Better understanding the impact of these regulators in survival to drug treatment might contribute to identify new drug targets and/or to design new strategies of intervention.

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Section: Whib Family (Whib1-7)mentioning

confidence: 99%

Section: Gntr Family Transcriptional Regulatorsmentioning

confidence: 99%

Transcriptional regulation and drug resistance in Mycobacterium tuberculosis

Miotto

Sorrentino

Giorgi

et al. 2022

Front. Cell. Infect. Microbiol.

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Inosine reverses multidrug resistance in Gram-negative bacteria carrying mobilized RND-type efflux pump gene cluster tmexCD-toprJ

Li,

Xu,

Fang

et al. 2024

mSystems

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Antimicrobial resistance is rapidly increasing worldwide, highlighting the urgent need for pharmaceutical and nonpharmaceutical interventions to tackle different-to-treat bacterial infections. Tigecycline, a semi-synthesis glycylcycline for parenteral administration, is widely recognized as one of the few effective therapies available against pan-drug resistant Gram-negative pathogens. Regrettably, the efficacy of multiple drugs, including tigecycline, is currently being undermined due to the emergence of a recently discovered mobilized resistance-nodulation-division-type efflux pump gene cluster tmexCD1-toprJ1 . Herein, by employing untargeted metabolomic approaches, we reveal that the expression of tmexCD1-toprJ1 disrupts bacterial purine metabolism, with inosine being identified as a crucial biomarker. Notably, the supplementation of inosine effectively reverses tigecycline resistance in tmexCD1-toprJ1 -positive bacteria. Mechanistically, exogenous inosine enhanced bacterial proton motive force, which promotes the uptake of tigecycline. Furthermore, inosine enhances succinate biosynthesis by stimulating the tricarboxylic acid cycle. Succinate interacts with the two-component system EnvZ/OmpR and upregulates OmpK 36, thereby promoting the influx of tigecycline. These actions collectively lead to the increased intracellular accumulation of tigecycline. Overall, our study offers a distinct combinational strategy to manage infections caused by tmexCD-toprJ -positive bacteria. IMPORTANCE TMexCD1-TOprJ1, a mobilized resistance-nodulation-division-type efflux pump, confers phenotypic resistance to multiple classes of antibiotics. Nowadays, tmexCD-toprJ has disseminated among diverse species of clinical pathogens, exacerbating the need for novel anti-infective strategies. In this study, we report that tmexCD1-toprJ1 -negative and -positive bacteria exhibit significantly different metabolic flux and characteristics, especially in purine metabolism. Intriguingly, the addition of inosine, a purine metabolite, effectively restores the antibacterial activity of tigecycline by promoting antibiotic uptake. Our findings highlight the correlation between bacterial mechanism and antibiotic resistance, and offer a distinct approach to overcome tmexCD-toprJ -mediated multidrug resistance.

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Dynamic Transcriptional Landscape of Mycobacterium smegmatis under Cold Stress

Grigorov

Skvortsova

Bychenko

et al. 2023

IJMS

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Bacterial adaptation to cold stress requires wide transcriptional reprogramming. However, the knowledge of molecular mechanisms underlying the cold stress response of mycobacteria is limited. We conducted comparative transcriptomic analysis of Mycobacterium smegmatis subjected to cold shock. The growth of M. smegmatis cultivated at 37oC was arrested just after exposure to cold (acclimation phase) but later (by 24 h) was resumed at a much slower rate (adaptation phase). Transcriptomic analyses revealed distinct gene expression patterns corresponding to the two phases. During the acclimation phase, differential expression was observed for genes associated with cell wall remodeling, starvation response, and osmotic pressure stress, in parallel with global changes in the expression of transcription factors and the downregulation of ribosomal genes, suggesting an energy-saving strategy to support survival. At the adaptation phase, the expression profiles were recovered, indicating restoration of the processes repressed earlier. Comparison of transcriptional responses in M. smegmatis with those in other bacteria revealed unique adaptation strategies developed by mycobacteria. Our findings shed light on the molecular mechanisms underlying M. smegmatis survival under cold stress. Further research should clarify whether the discovered transcriptional mechanisms exist in other mycobacterial species, including pathogenic Mycobacterium tuberculosis, which could be important for transmission control.

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Deficiency of GntR Family Regulator MSMEG_5174 Promotes Mycobacterium smegmatis Resistance to Aminoglycosides via Manipulating Purine Metabolism

Cited by 3 publications

References 46 publications

Transcriptional regulation and drug resistance in Mycobacterium tuberculosis

Transcriptional regulation and drug resistance in Mycobacterium tuberculosis

Inosine reverses multidrug resistance in Gram-negative bacteria carrying mobilized RND-type efflux pump gene cluster tmexCD-toprJ

Dynamic Transcriptional Landscape of Mycobacterium smegmatis under Cold Stress

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