Intrinsic rifamycin resistance of<i>Mycobacterium abscessus</i>is mediated by ADP-ribosyltransferase MAB_0591

Rominski, Anna; Roditscheff, Anna; Selchow, Petra; Böttger, Erik C.; Sander, Peter

doi:10.1093/jac/dkw466

Cited by 109 publications

(121 citation statements)

References 44 publications

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“…However, resistance to streptomycin was unaffected (data not shown). This is in agreement with observations of Rominski et al, who recently showed that a deletion of MAB_4532c results in amikacin and kanamycin sensitivity (37). Kanamycin resistance of M. tuberculosis has been previously attributed to a member encoding GNAT family acetyltransferases, eis1 (38).…”

Section: Resultssupporting

confidence: 92%

“…Kanamycin resistance of M. tuberculosis has been previously attributed to a member encoding GNAT family acetyltransferases, eis1 (38). Sequence analysis suggests that MAB_4532c belongs to the GNAT family of acetyltransferases with 29% homology to M. abscessus eis1 (MAB_4124) and is referred to as eis2 (37). Interestingly, both paralogs of eis, eis1 (MSMEG_3513) and eis2 (MSMEG_4540), are found in M. smegmatis.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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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“…Understanding the mechanistic basis of the activity differences may open new avenues to inform medicinal chemistry efforts and discover more potent rifamycins for the treatment of mycobacterial infections. Interestingly, Rominski and colleagues (50) recently showed via elegant genetic studies, including heterologous expression and gene knockout studies, that MAB_0591 , encoding a putative rifampin ADP-ribosyltransferase (48, 51–53), is a major contributor to the high level of intrinsic rifampin resistance in M. abscessus subsp.…”

Section: Discussionmentioning

confidence: 99%

“…abscessus subsp. abscessus ATCC 19977 (50). It remains to be determined whether rifabutin is less metabolized by this or other putative rifampin-metabolizing enzymes, such as FAD monooxygenases (51, 54, 55), or whether the differential antibacterial activity of the rifamycins against M.…”

Section: Discussionmentioning

confidence: 99%

Rifabutin Is Active against Mycobacterium abscessus Complex

Aziz

Low

et al. 2017

Antimicrob Agents Chemother

129

167

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Lung infections caused by Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and to other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug-resistant pathogen showing resistance to even standard antituberculosis drugs, such as rifampin. Here, our objective was to identify existing drugs that may be employed for the treatment of M. abscessus lung disease. A collection of more than 2,700 approved drugs was screened at a single-point concentration against an M. abscessus clinical isolate. Hits were confirmed with fresh solids in dose-response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three M. abscessus subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampin derivative rifabutin had MICs of 3 ± 2 μM (3 μg/ml) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T, and M. abscessus subsp. massiliense CCUG 48898-T, as well as against a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin-resistant strains. In conclusion, rifabutin, in contrast to rifampin, is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

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“…A commonly used counterselectable marker in mycobacteria, sacB, which confers susceptibility to sucrose, does not work in M. abscessus for allelic exchange [16]. A recent report described the use of isoniazid counterselection for allelic exchange in M. abscessus [20].…”

Section: Introductionmentioning

confidence: 99%

galK-based suicide vector mediated allelic exchange in Mycobacterium abscessus

2017

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Mycobacterium abscessus is a fast-growing environmental organism and an important emerging pathogen. It is highly resistant to many antibiotics and undergoes a smooth to rough colony morphology change that appears to be important for pathogenesis. Smooth environmental strains have a glycopeptidolipid (GPL) on the surface, while certain types of clinical strains are often rough and lack this GPL, due to mutations in biosynthetic genes or the mmpL4b transporter gene. We report here the development and evaluation of an allelic exchange system for unmarked alleles in M. abscessus ATCC19977, using a suicide vector bearing the E. coli galK gene and 2-deoxygalactose counterselection. We describe here two variant galK suicide vectors, and demonstrate their utility in constructing a variety of mutants with deletion alleles of the mmpL4b GPL transporter gene, the mbtH GPL biosynthesis gene, the known b-lactamase gene MAB_2875 and a putative b-lactamase gene, MAB_2833. We also show that a novel allele of the E. coli aacC4 gene, conferring apramycin resistance (aacC41), can be used as a selectable marker in M. abscessus ATCC19977 at single copy.

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Intrinsic rifamycin resistance ofMycobacterium abscessusis mediated by ADP-ribosyltransferase MAB_0591

Cited by 109 publications

References 44 publications

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

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

Rifabutin Is Active against Mycobacterium abscessus Complex

galK-based suicide vector mediated allelic exchange in Mycobacterium abscessus

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