Mycobacterium tuberculosis Rv0191 is an efflux pump of major facilitator superfamily transporter regulated by Rv1353c

Xue, Li; Li, Ping; Ruan, Cao; Xie, Long xiang; Gu, Yinzhong; Jiang, Li; Qin, Yi; Lv, Xi; Xie, Jianping

doi:10.1016/j.abb.2019.04.010

Cited by 9 publications

(7 citation statements)

References 55 publications

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“…Therefore, we wanted to determine if tolerance of Spm by M.tb was supported by general efflux activities or by specific efflux pumps. To achieve that, we generated an in-frame unmarked deletion of rv1877 ( Figures 1A , B ; Supplementary Figures S1A,B ) and in-frame unmarked deletion of rv0191 in M.tb ( Figures 1C , D ; Supplementary Figures S1A,D ) since Rv0191 is an efflux pump that seems to be able to extrude only chloramphenicol ( Li et al, 2019 ). Moreover, since Rv1878 was found not to be essential for Spm detoxification ( Krysenko et al, 2023 ), we sought to investigate its physiological role.…”

Section: Resultsmentioning

confidence: 99%

“…This was because rv1877 is located upstream rv1878 , is co-transcribed with rv1878 and other genes in the cluster ( Harth et al, 2005 ) and they may therefore have overlapping physiological roles though not necessarily during Spm stress. Furthermore, to investigate if tolerance to Spm was facilitated by any efflux pump, or may be specific to multi-drug efflux pumps such as Rv1877 ( Adhikary et al, 2022 ) and Rv3065 ( Rodrigues et al, 2013 ), we generated a ∆ rv0191 mutant, where rv0191 codes for an efflux pump which seems not be a multi-drug pump, but is more specific to chloramphenicol ( Li et al, 2019 ). We first examined their transcriptomic profile and found that the ∆ rv1877 and ∆ rv1878 mutants displayed almost similar transcriptomic profiles ( Table 1 ), as genes encoding enzymes involved in dormancy, hypoxia, C/N, iron and lipid metabolism were upregulated in both strains (see Results section, Supplementary Tables S3, S4 ), suggesting they could have overlapping functions in these physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

“…However, since we aimed to follow-up on the investigation of the physiological role of Rv1878 while assessing if Spm is detoxified by multi-drug efflux pumps, we chose to investigate the role of Rv1877 in the context of Spm detoxification and in the context of any overlapping physiological role it may have with Rv1878 since they are encoded by neighborhood genes that are co-transcribed ( Harth et al, 2005 ). In order to determine if tolerance of Spm by M.tb is supported by other efflux pumps, we also investigated the role of Rv0191 which encodes a more specific MFS-type efflux pump ( de Rossi et al, 2002 ; Li et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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The efflux pumps Rv1877 and Rv0191 play differential roles in the protection of Mycobacterium tuberculosis against chemical stress

Sao Emani,

Reiling

2024

Front. Microbiol.

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BackgroundIt was previously shown that GlnA3sc enabled Streptomyces coelicolor to survive in excess polyamines. However, subsequent studies revealed that Rv1878, the corresponding Mycobacterium tuberculosis (M.tb) ortholog, was not essential for the detoxification of spermine (Spm), in M.tb. On the other hand, the multi-drug efflux pump Rv1877 was previously shown to enable export of a wide range of compounds, while Rv0191 was shown to be more specific to chloramphenicol.RationaleTherefore, we first wanted to determine if detoxification of Spm by efflux can be achieved by any efflux pump, or if that was dependent upon the function of the pump. Next, since Rv1878 was found not to be essential for the detoxification of Spm, we sought to follow-up on the investigation of the physiological role of Rv1878 along with Rv1877 and Rv0191.ApproachTo evaluate the specificity of efflux pumps in the mycobacterial tolerance to Spm, we generated unmarked ∆rv1877 and ∆rv0191 M.tb mutants and evaluated their susceptibility to Spm. To follow up on the investigation of any other physiological roles they may have, we characterized them along with the ∆rv1878 M.tb mutant.ResultsThe ∆rv1877 mutant was sensitive to Spm stress, while the ∆rv0191 mutant was not. On the other hand, the ∆rv1878 mutant grew better than the wild-type during iron starvation yet was sensitive to cell wall stress. The proteins Rv1877 and Rv1878 seemed to play physiological roles during hypoxia and acidic stress. Lastly, the ∆rv0191 mutant was the only mutant that was sensitive to oxidative stress.ConclusionThe multidrug MFS-type efflux pump Rv1877 is required for Spm detoxification, as opposed to Rv0191 which seems to play a more specific role. Moreover, Rv1878 seems to play a role in the regulation of iron homeostasis and the reconstitution of the cell wall of M.tb. On the other hand, the sensitivity of the ∆rv0191 mutant to oxidative stress, suggests that Rv0191 may be responsible for the transport of low molecular weight thiols.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The efflux pumps Rv1877 and Rv0191 play differential roles in the protection of Mycobacterium tuberculosis against chemical stress

Sao Emani,

Reiling

2024

Front. Microbiol.

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“…(Figure 2A). The MFS transporter is one of five main families of multidrug efflux pumps (da Silva et al, 2011; Li et al, 2019). Reported CHL resistance genes classified as MFS transporters include cmlA , floR , fexA , pexA , fexB , mdfA and Rv0191 (Edgar & Bibi, 1997; Li et al, 2013; Li et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The MFS transporter is one of five main families of multidrug efflux pumps (da Silva et al, 2011; Li et al, 2019). Reported CHL resistance genes classified as MFS transporters include cmlA , floR , fexA , pexA , fexB , mdfA and Rv0191 (Edgar & Bibi, 1997; Li et al, 2013; Li et al, 2019). To verify the function of mfS LMS , mfS QY071 and mfS L‐11A , clones of the three genes ligated to the T‐vector pMD19 were spotted on LB plates containing 50 mg L −1 CHL.…”

Section: Discussionmentioning

confidence: 99%

ChlOR, a GMC family oxidoreductase that evolved independently from the actinomycete, confers resistance to amphenicol antibiotics

Qian,

Cheng,

Lai

et al. 2023

Environmental Microbiology

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Overuse of the amphenicol antibiotics chloramphenicol (CHL) and thiamphenicol (TAP) poses a great threat to ecosystem safety and human health. The strain, Nocardioides sp. LMS‐CY, Nocardioides sp. QY071 and Nocardioides sp. L‐11A, classified as a gram‐positive actinomycete, harbours a complete CHL metabolic pathway. However, the metabolic genes (clusters) involved in the entire pathway in gram‐positive actinomycetes are still limited. Here, chlORLMS, chlORQY071 and chlORL‐11A completely from the actinomycete Nocardioides spp. were found to act on the C1‐OH of the CHL/TAP side chain, directly converting CHL/TAP to 4‐nitrobenzaldehyde (PNBD)/4‐methylsulfonyl benzaldehyde (PMBD) and transforming PNBD/PMBD into 4‐nitrobenzyl alcohol (PNBM)/4‐methylsulfonyl phenyl methanol (PMBM). Furthermore, oxidoreductases can transform PNBM into 4‐nitrobenzoate (PNBA). The oxidoreductases ChlORLMS, ChlORQY071 and ChlORL‐11A were all classified as cellobiose dehydrogenases from the glucose methanol choline (GMC) family. Based on the Swiss‐Prot database, ChlORQY071 exhibited a lower identity (27.12%–35.10% similarity) with the reported oxidoreductases. Enzymatic and molecular docking analyses showed that ChlORQY071 and ChlORL‐11A from the two similar genomes were remarkably more effective in metabolizing CHL than ChlORLMS. Overall, the detailed resistance mechanism of CHL/TAP by actinomycete strains isolated from soil and livestock manure will provide insights into the occurrence of CHL/TAP resistance genes in the environment, resistance risk and bioremediation of CHL/TAP‐contaminated environments.

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TetR and OmpR family regulators in natural product biosynthesis and resistance

Patil,

Sharma,

Bhaskarwar

et al. 2023

Proteins

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This article provides a comprehensive review and sequence‐structure analysis of transcription regulator (TR) families, TetR and OmpR/PhoB, involved in specialized secondary metabolite (SSM) biosynthesis and resistance. Transcription regulation is a fundamental process, playing a crucial role in orchestrating gene expression to confer a survival advantage in response to frequent environmental stress conditions. This process, coupled with signal sensing, enables bacteria to respond to a diverse range of intra and extracellular signals. Thus, major bacterial signaling systems use a receptor domain to sense chemical stimuli along with an output domain responsible for transcription regulation through DNA‐binding. Sensory and output domains on a single polypeptide chain (one component system, OCS) allow response to stimuli by allostery, that is, DNA‐binding affinity modulation upon signal presence/absence. On the other hand, two component systems (TCSs) allow cross‐talk between the sensory and output domains as they are disjoint and transmit information by phosphorelay to mount a response. In both cases, however, TRs play a central role. Biosynthesis of SSMs, which includes antibiotics, is heavily regulated by TRs as it diverts the cell's resources towards the production of these expendable compounds, which also have clinical applications. These TRs have evolved to relay information across specific signals and target genes, thus providing a rich source of unique mechanisms to explore towards addressing the rapid escalation in antimicrobial resistance (AMR). Here we focus on the TetR and OmpR family TRs, which belong to OCS and TCS, respectively. These TR families are well‐known examples of regulators in secondary metabolism and are ubiquitous across different bacteria, as they also participate in a myriad of cellular processes apart from SSM biosynthesis and resistance. As a result, these families exhibit higher sequence divergence, which is also evident from our bioinformatic analysis of 158 389 and 77 437 sequences from TetR and OmpR family TRs, respectively. The analysis of both sequence and structure allowed us to identify novel motifs in addition to the known motifs responsible for TR function and its structural integrity. Understanding the diverse mechanisms employed by these TRs is essential for unraveling the biosynthesis of SSMs. This can also help exploit their regulatory role in biosynthesis for significant pharmaceutical, agricultural, and industrial applications.

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Mycobacterium tuberculosis Rv0191 is an efflux pump of major facilitator superfamily transporter regulated by Rv1353c

Cited by 9 publications

References 55 publications

The efflux pumps Rv1877 and Rv0191 play differential roles in the protection of Mycobacterium tuberculosis against chemical stress

The efflux pumps Rv1877 and Rv0191 play differential roles in the protection of Mycobacterium tuberculosis against chemical stress

ChlOR, a GMC family oxidoreductase that evolved independently from the actinomycete, confers resistance to amphenicol antibiotics

TetR and OmpR family regulators in natural product biosynthesis and resistance

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