WhiB7, an Fe-S-dependent Transcription Factor That Activates Species-specific Repertoires of Drug Resistance Determinants in Actinobacteria

Ramón-García, Santiago; Ng, Carol; Jensen, Pernille Rose; Dosanjh, Manisha; Burian, Ján; Morris, Rowan P.; Folcher, Marc; Eltis, Lindsay D.; Grzesiek, Stephan; Nguyen, Liem; Thompson, Charles J.

doi:10.1074/jbc.m113.516385

Cited by 52 publications

(57 citation statements)

References 81 publications

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“…While previous work found that Lsr2 regulates expression of the drug efflux pump IniBAC (Colangeli et al 2005, 2007), more recent studies suggested that Lsr2 also protects M. tuberculosis from oxidative stress (Bartek et al 2014; Colangeli et al 2009). WhiB7 is a MDR transcription regulator exclusively found in Actinobacteria including mycobacteria (Morris et al 2005; Ramon-Garcia et al 2013). Deletion of whiB7 leads to increased sensitivity to multiple antibiotics whereas overexpression results in enhanced resistance (Morris et al 2005).…”

Section: Bactericidal Activity Of Drugs and Oxidative Stress In Mycobmentioning

confidence: 99%

Antibiotic resistance mechanisms in M. tuberculosis: an update

2016

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Treatment of tuberculosis (TB) has been a therapeutic challenge because of not only the naturally high resistance level of Mycobacterium tuberculosis to antibiotics but also the newly acquired mutations that confer further resistance. Currently standardized regimens require patients to daily ingest up to four drugs under direct observation of a healthcare worker for a period of 6–9 months. Although they are quite effective in treating drug susceptible TB, these lengthy treatments often lead to patient non-adherence, which catalyzes for the emergence of M. tuberculosis strains that are increasingly resistant to the few available anti-TB drugs. The rapid evolution of M. tuberculosis, from mono-drug-resistant to multiple drug-resistant, extensively drug-resistant and most recently totally drug-resistant strains, is threatening to make TB once again an untreatable disease if new therapeutic options do not soon become available. Here, I discuss the molecular mechanisms by which M. tuberculosis confers its profound resistance to antibiotics. This knowledge may help in developing novel strategies for weakening drug resistance, thus enhancing the potency of available antibiotics against both drug susceptible and resistant M. tuberculosis strains.

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Section: Bactericidal Activity Of Drugs and Oxidative Stress In Mycobmentioning

confidence: 99%

Antibiotic resistance mechanisms in M. tuberculosis: an update

2016

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“…WhiB7 and its orthologue, WblC, control innate multi-drug resistance in Mycobacteria and Streptomyces respectively (Morris et al, 2005;Ramon-Garcia et al, 2013). There is no obvious orthologue in Corynebacteria (Table 2 and Fig.…”

Section: Class V (Whib7/wblc)mentioning

confidence: 99%

The actinobacterial WhiB‐like (Wbl) family of transcription factors

Bush

2018

Molecular Microbiology

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SummaryThe WhiB‐like (Wbl) family of proteins are exclusively found in Actinobacteria. Wbls have been shown to play key roles in virulence and antibiotic resistance in Mycobacteria and Corynebacteria, reflecting their importance during infection by the human pathogens Mycobacterium tuberculosis, Mycobacterium leprae and Corynebacterium diphtheriae. In the antibiotic‐producing Streptomyces, several Wbls have important roles in the regulation of morphological differentiation, including WhiB, a protein that controls the initiation of sporulation septation and the founding member of the Wbl family. In recent years, genome sequencing has revealed the prevalence of Wbl paralogues in species throughout the Actinobacteria. Wbl proteins are small (generally ~80–140 residues) and each contains four invariant cysteine residues that bind an O2‐ and NO‐sensitive [4Fe–4S] cluster, raising the question as to how they can maintain distinct cellular functions within a given species. Despite their discovery over 25 years ago, the Wbl protein family has largely remained enigmatic. Here I summarise recent research in Mycobacteria, Corynebacteria and Streptomyces that sheds light on the biochemical function of Wbls as transcription factors and as potential sensors of O2 and NO. I suggest that Wbl evolution has created diversity in protein–protein interactions, [4Fe–4S] cluster‐sensitivity and the ability to bind DNA.

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“…One of the best studied regulators of this reprogramming circuit is WhiB7, a transcriptional activator that belongs to the WhiB family of transcriptional regulators conserved in actinomycetes (29,30). WhiB7 proteins have a variable N terminus and a conserved core sequence characterized by four iron-binding conserved cysteine residues, a G/Y-rich motif, and a positively charged AT-hook that binds an AT-rich region in DNA (31). whiB7 is induced in the presence of several structurally unrelated antibiotics, such as tetracycline, macrolides, and aminoglycosides, as well as compounds that perturb respiration, redox balance, and iron starvation (30)(31)(32)(33)(34).…”

mentioning

confidence: 99%

“…WhiB7 proteins have a variable N terminus and a conserved core sequence characterized by four iron-binding conserved cysteine residues, a G/Y-rich motif, and a positively charged AT-hook that binds an AT-rich region in DNA (31). whiB7 is induced in the presence of several structurally unrelated antibiotics, such as tetracycline, macrolides, and aminoglycosides, as well as compounds that perturb respiration, redox balance, and iron starvation (30)(31)(32)(33)(34). A deletion of whiB7 in Mycobacterium smegmatis and Mycobacterium tuberculosis results in multidrug sensitivity (34).…”

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Mycobacterium abscessus WhiB7 Regulates a Species-Specific Repertoire of Genes To Confer Extreme Antibiotic Resistance

Hurst-Hess

Rudra

Ghosh

2017

Antimicrob Agents Chemother

134

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causes acute and chronic bronchopulmonary infection in patients with chronic lung damage, of which cystic fibrosis (CF) patients are particularly vulnerable. The major threat posed by this organism is its high intrinsic antibiotic resistance. A typical treatment regimen involves a 6- to 12-month-long combination therapy of clarithromycin and amikacin, with cure rates below 50% and multiple side effects, especially due to amikacin. In the present work, we show that , a homologue of and with previously demonstrated effects on intrinsic antibiotic resistance, is strongly induced when exposed to clinically relevant antibiotics that target the ribosome: erythromycin, clarithromycin, amikacin, tetracycline, and spectinomycin. The deletion of results in sensitivity to all of the above-mentioned antibiotics. Further, we have defined and compared the regulon of with the closely related nontuberculous mycobacterium (NTM) to demonstrate the induction of a species-specific repertoire of genes. Finally, we show that one such gene,, is specifically induced in by and contributes to its higher levels of intrinsic amikacin resistance. This species-specific pattern of gene induction might account for the differences in drug susceptibilities to other antibiotics and between different mycobacterial species.

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WhiB7, an Fe-S-dependent Transcription Factor That Activates Species-specific Repertoires of Drug Resistance Determinants in Actinobacteria

Cited by 52 publications

References 81 publications

Antibiotic resistance mechanisms in M. tuberculosis: an update

Antibiotic resistance mechanisms in M. tuberculosis: an update

The actinobacterial WhiB‐like (Wbl) family of transcription factors

Mycobacterium abscessus WhiB7 Regulates a Species-Specific Repertoire of Genes To Confer Extreme Antibiotic Resistance

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