Ribosylative inactivation of rifampin by Mycobacterium smegmatis is a principal contributor to its low susceptibility to this antibiotic

Quan, Selwyn; Venter, Heidi; Dabbs, Eric R.

doi:10.1128/aac.41.11.2456

Cited by 101 publications

(60 citation statements)

References 34 publications

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“…Serial dilution plate counts determined this to correspond to 3.8e8 CFU/mL. The Minimal Inhibitory Concentration (MIC) was reported in the literature26 to be 20 μg/mL and this was confirmed by visual MIC assays. Various multiples of this concentration, including 1/4X, 1/2X, 1X, 2X and 5X this MIC were tested for growth effects through growth curves (1X and 2X in Supplementary Fig.…”

Section: Resultssupporting

confidence: 56%

A temporal proteome dynamics study reveals the molecular basis of induced phenotypic resistance in Mycobacterium smegmatis at sub-lethal rifampicin concentrations

Giddey

Kock

Nakedi

et al. 2017

Sci Rep

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In the last 40 years only one new antitubercular drug has been approved, whilst resistance to current drugs, including rifampicin, is spreading. Here, we used the model organism Mycobacterium smegmatis to study mechanisms of phenotypic mycobacterial resistance, employing quantitative mass spectrometry-based proteomics to investigate the temporal effects of sub-lethal concentrations of rifampicin on the mycobacterial proteome at time-points corresponding to early response, onset of bacteriostasis and early recovery. Across 18 samples, a total of 3,218 proteins were identified from 31,846 distinct peptides averaging 16,250 identified peptides per sample. We found evidence that two component signal transduction systems (e.g. MprA/MprB) play a major role during initial mycobacterial adaptive responses to sub-lethal rifampicin and that, after dampening an initial SOS response, the bacteria supress the DevR (DosR) regulon and also upregulate their transcriptional and translational machineries. Furthermore, we found a co-ordinated dysregulation in haeme and mycobactin synthesis. Finally, gradual upregulation of the M. smegmatis-specific rifampin ADP-ribosyl transferase was observed which, together with upregulation of transcriptional and translational machinery, likely explains recovery of normal growth. Overall, our data indicates that in mycobacteria, sub-lethal rifampicin triggers a concerted phenotypic response that contrasts significantly with that observed at higher antimicrobial doses.

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Section: Resultssupporting

confidence: 56%

A temporal proteome dynamics study reveals the molecular basis of induced phenotypic resistance in Mycobacterium smegmatis at sub-lethal rifampicin concentrations

Giddey

Kock

Nakedi

et al. 2017

Sci Rep

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“…2). We are investigating whether the difference in their antibacterial activities is due to differences in intrabacterial pharmacokinetic properties of the rifamycin derivatives, i.e., differences in bacterial drug uptake, efflux, or metabolism (45, 48, 49). 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.…”

Section: Discussionmentioning

confidence: 99%

Rifabutin Is Active against Mycobacterium abscessus Complex

Aziz

Low

et al. 2017

Antimicrob Agents Chemother

130

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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“…It has been reported that M. smegmatis is naturally resistant to RIF even though no mutations have been characterized in the RIF resistance-determining region of the rpoB gene [1], [23]. Although some evidence has shown that RIF inactivation via ribosylation may be a principal mechanism of RIF resistance in M. smegmatis , this mechanism cannot solely account for its high level of RIF resistance [1], [23].…”

Section: Discussionmentioning

confidence: 99%

“…Although some evidence has shown that RIF inactivation via ribosylation may be a principal mechanism of RIF resistance in M. smegmatis , this mechanism cannot solely account for its high level of RIF resistance [1], [23]. It has been demonstrated that porin MspA plays an important role in the influx of quaternary ammonium compounds and antibiotics in M. smegmatis [24]; however, the efficacy of rifampicin against M. smegmatis is not strongly affected by the absence of porin [25], implying that other unknown mechanisms are involved in the regulation of rifampicin resistance in M. smegmatis .…”

Section: Discussionmentioning

confidence: 99%

A Novel marRAB Operon Contributes to the Rifampicin Resistance in Mycobacterium smegmatis

et al. 2014

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The multiple-antibiotic resistance regulator (MarR) plays an important role in modulating bacterial antibiotic resistance. However, the regulatory model of the marRAB operon in mycobacteria remains to be characterized. Here we report that a MarR, encoded by Ms6508, and its marRAB operon specifically contribute to rifampicin (RIF) resistance in Mycobacterium smegmatis. We show that the MarR recognizes a conserved 21-bp palindromic motif and negatively regulates the expression of two ABC transporters in the operon, encoded by Ms6509–6510. Unlike other known drug efflux pumps, overexpression of these two ABC transporters unexpectedly increased RIF sensitivity and deletion of these two genes increased mycobacterial resistance to the antibiotic. No change can be detected for the sensitivity of recombinant mycobacterial strains to three other anti-TB drugs. Furthermore, HPLC experiments suggested that Ms6509–Ms6510 could pump RIF into the mycobacterial cells. These findings indicated that the mycobacterial MarR functions as a repressor and constitutively inhibits the expression of the marRAB operon, which specifically contributes to RIF resistance in M. smegmatis. Therefore, our data suggest a new regulatory mechanism of RIF resistance and also provide the new insight into the regulatory model of a marRAB operon in mycobacteria.

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Ribosylative inactivation of rifampin by Mycobacterium smegmatis is a principal contributor to its low susceptibility to this antibiotic

Cited by 101 publications

References 34 publications

A temporal proteome dynamics study reveals the molecular basis of induced phenotypic resistance in Mycobacterium smegmatis at sub-lethal rifampicin concentrations

A temporal proteome dynamics study reveals the molecular basis of induced phenotypic resistance in Mycobacterium smegmatis at sub-lethal rifampicin concentrations

Rifabutin Is Active against Mycobacterium abscessus Complex

A Novel marRAB Operon Contributes to the Rifampicin Resistance in Mycobacterium smegmatis

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