Mupirocin-Induced Mutations in ileS in Various Genetic Backgrounds of Methicillin-Resistant Staphylococcus aureus

Abstract

Topical mupirocin is widely used for the decolonization of methicillin-resistant Staphylococcus aureus (MRSA) carriers. We evaluated the capacity of various MRSA clonotypes to develop mutations in the ileS gene associated with low-level mupirocin resistance. Twenty-four mupirocin-sensitive MRSA isolates from a variety of genotypes (determined by a multilocus variablenumber tandem-repeat assay) were selected. Mupirocin MICs were determined by Etest. The isolates were then incubated in subinhibitory concentrations of mupirocin for 7 to 14 days. Repeat MIC determinations and sequencing of the ileS gene were then performed. Doubling times of isolates exposed to mupirocin and of unexposed isolates were compared. We found that exposure to mupirocin led to rapid induction of low-level resistance (MICs of 8 to 24 g/ml) in 11 of 24 (46%) MRSA isolates. This phenomenon was observed in strains with diverse genetic backgrounds. Various mutations were detected in 18 of 24 (75%) MRSA isolates. Acquisition of mutations appeared to be a stepwise process during prolonged incubation with the drug. Among the five isolates exhibiting low-level resistance and the highest MICs, four tested sensitive after incubation in the absence of mupirocin but there was no reversion to the susceptible wild-type primary sequence. Resistance was not associated with significant fitness cost, suggesting that MRSA strains with low-level mupirocin resistance may have a selective advantage in facilities where mupirocin is commonly used. Our findings emphasize the importance of the judicious use of this topical agent and the need to closely monitor for the emergence of resistance.

Current and Emerging Topical Antibacterials and Antiseptics: Agents, Action, and Resistance Patterns

“…At the molecular level, low-level resistance (indicated by MICs of 8 to 256 mg/ml) is determined by point mutations in the isoleucyl-tRNA synthetase gene (ileS) (76,(83)(84)(85)(86), which is chromosomally borne (in contrast to plasmid borne). A range of point mutations have been associated with low-level resistance, with the most commonly reported mutations being V588F and V631F (74,76,87). These mutations are located in the Rossman fold, thereby limiting the ability of mupirocin to bind to the isoleucyl-tRNA synthetase enzyme (76).…”

“…These mutations are located in the Rossman fold, thereby limiting the ability of mupirocin to bind to the isoleucyl-tRNA synthetase enzyme (76). Importantly, the presence of these mutations has not been shown to confer a significant bacterial fitness cost in vitro, suggesting a possible fitness advantage for these low-level resistant strains in the context of ongoing mupirocin use (84,85,87). Interestingly, one recent study demonstrated the rapid development of mutations associated with low-level mupirocin resistance after only 14 days of exposure to subinhibitory mupirocin concentrations, with mutations being stably maintained in the absence of mupirocin (87).…”

Neomycin Sulfate Improves the Antimicrobial Activity of Mupirocin-Based Antibacterial Ointments

“…Low-level mupirocin-resistant (LL-MR) S. aureus strains are defined as exhibiting an MIC of 8 to 256 g ml Ϫ1 due to point mutations in the organism's native isoleucyl-tRNA synthetase gene (ileRS) and develop rapidly in both the laboratory and clinical settings (28). High-level mupirocin resistance (HL-MR) (MIC of Ͼ256 g ml Ϫ1 ) occurs less frequently and is attributable to the acquisition of a mobile genetic element harboring either mupA, which codes for an alternate isoleucyl-tRNA synthetase, or the less-characterized mupB gene (29,30).…”

Prevalence and molecular characterization of methicillin-resistant Staphylococcus aureus with mupirocin, fusidic acid and/or retapamulin resistance

“…to 350 described by Lee et al [24]. The N213D mutation had been previously reported, and are considered to have no impact on the sensitivity of MUP [25].…”

“…In addition, no other mutations in IleS were found. Lee et al [24] reported that a mutation of S634F could confer phenotype of susceptibility or MuL in diverse isolates. In view of this phenomenon, the contribution of N213D mutation to MuL should be evaluated further.…”