Mycobacterium tuberculosis Rv1152 is a Novel GntR Family Transcriptional Regulator Involved in Intrinsic Vancomycin Resistance and is a Potential Vancomycin Adjuvant Target

Zeng, Jie; Deng, Wanyan; Yang, Wenmin; Luo, Hongping; Duan, Xiangke; Xie, Longxiang; Li, Ping; Wang, Rui; Fu, Tiwei; Abdalla, Abualgasim Elgaili

doi:10.1038/srep28002

Cited by 17 publications

(17 citation statements)

References 49 publications

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“…it is known that GntR-family proteins are involved in resistance to antimicrobial compounds. In detail, overexpression of the GntR-family protein Rv1152 from M. tuberculosis results in higher resistance towards vancomycin [ 50 ]. In M. smegmatis overexpression of the GntR-family protein Ms0535 leads to enhanced resistance towards isoniazid, whose metabolite inhibits cell wall synthesis [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Signatures of Clostridium difficile Stressed with Metronidazole, Vancomycin, or Fidaxomicin

Maaß

Otto

Albrecht

et al. 2018

Cells

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The anaerobic pathogen Clostridium difficile is of growing significance for the health care system due to its increasing incidence and mortality. As C. difficile infection is both supported and treated by antibiotics, a deeper knowledge on how antimicrobial agents affect the physiology of this important pathogen may help to understand and prevent the development and spreading of antibiotic resistant strains. As the proteomic response of a cell to stress aims at counteracting the harmful effects of this stress, it can be expected that the pattern of a pathogen’s responses to antibiotic treatment will be dependent on the antibiotic mechanism of action. Hence, every antibiotic treatment is expected to result in a specific proteomic signature characterizing its mode of action. In the study presented here, the proteomic response of C. difficile 630∆erm to vancomycin, metronidazole, and fidaxomicin stress was investigated on the level of protein abundance and protein synthesis based on 2D PAGE. The quantification of 425 proteins of C. difficile allowed the deduction of proteomic signatures specific for each drug treatment. Indeed, these proteomic signatures indicate very specific cellular responses to each antibiotic with only little overlap of the responses. Whereas signature proteins for vancomycin stress fulfil various cellular functions, the proteomic signature of metronidazole stress is characterized by alterations of proteins involved in protein biosynthesis and protein degradation as well as in DNA replication, recombination, and repair. In contrast, proteins differentially expressed after fidaxomicin treatment can be assigned to amino acid biosynthesis, transcription, cell motility, and the cell envelope functions. Notably, the data provided by this study hint also at so far unknown antibiotic detoxification mechanisms.

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Section: Discussionmentioning

confidence: 99%

Proteomic Signatures of Clostridium difficile Stressed with Metronidazole, Vancomycin, or Fidaxomicin

Maaß

Otto

Albrecht

et al. 2018

Cells

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“…Thus, induction of the rv2623 gene, by treatment with vancomycin, could contribute to the induction of persistent infection in the host and difficulty in eradicating the disease. Rv1152 is a transcriptional regulator that belongs to the GntR family and negatively regulates the vancomycin-responsive genes, including rv2623 (Zeng et al, 2016). The MIC of vancomycin against M. tuberculosis is too high to allow its use in the clinic, but the discovery of adjuvants to improve its efficacy, such as a Rv1152 inhibitor, should be envisaged.…”

Section: Transcriptional Signature and Drug Mode Of Actionmentioning

confidence: 99%

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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“…GntR family members fulfil various biological functions in diverse bacterial groups. Amongst others, GntR-like proteins are involved in resistance to antimicrobial compounds including vancomycin and isoniazid, which inhibit cell wall synthesis [ 59 , 60 , 61 ]. In this study, we found the GntR-like protein CDIF630erm_01007 with significantly altered amounts after the addition of nisin to C. difficile .…”

Section: Resultsmentioning

confidence: 99%

Proteomic Adaptation of Clostridioides difficile to Treatment with the Antimicrobial Peptide Nisin

Maaß

Bartel

Mücke

et al. 2021

Cells

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Clostridioides difficile is the leading cause of antibiotic-associated diarrhea but can also result in more serious, life-threatening conditions. The incidence of C. difficile infections in hospitals is increasing, both in frequency and severity, and antibiotic-resistant C. difficile strains are advancing. Against this background antimicrobial peptides (AMPs) are an interesting alternative to classic antibiotics. Information on the effects of AMPs on C. difficile will not only enhance the knowledge for possible biomedical application but may also provide insights into mechanisms of C. difficile to adapt or counteract AMPs. This study applies state-of-the-art mass spectrometry methods to quantitatively investigate the proteomic response of C. difficile 630∆erm to sublethal concentrations of the AMP nisin allowing to follow the cellular stress adaptation in a time-resolved manner. The results do not only point at a heavy reorganization of the cellular envelope but also resulted in pronounced changes in central cellular processes such as carbohydrate metabolism. Further, the number of flagella per cell was increased during the adaptation process. The potential involvement of flagella in nisin adaptation was supported by a more resistant phenotype exhibited by a non-motile but hyper-flagellated mutant.

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Mycobacterium tuberculosis Rv1152 is a Novel GntR Family Transcriptional Regulator Involved in Intrinsic Vancomycin Resistance and is a Potential Vancomycin Adjuvant Target

Cited by 17 publications

References 49 publications

Proteomic Signatures of Clostridium difficile Stressed with Metronidazole, Vancomycin, or Fidaxomicin

Proteomic Signatures of Clostridium difficile Stressed with Metronidazole, Vancomycin, or Fidaxomicin

Genome-Wide Transcriptional Responses of Mycobacterium to Antibiotics

Proteomic Adaptation of Clostridioides difficile to Treatment with the Antimicrobial Peptide Nisin

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