Abstract
BackgroundIn Staphylococcus aureus sub-populations of slow-growing cells forming small colony variants (SCVs) are associated with persistent and recurrent infections that are difficult to eradicate with antibiotic therapies. In SCVs that are resistant towards aminoglycosides, mutations have been identified in genes encoding components of the respiratory chain. Given the high frequencies of SCVs isolated clinically it is vital to understand the conditions that promote or select for SCVs.ResultsIn this study we have examined how exposure to sub-inhibitory concentrations of antibiotics with different mechanism of action influence the formation of SCVs that are resistant to otherwise lethal concentrations of the aminoglycoside, gentamicin. We found that exposure of S. aureus to fluoroquinolones and mitomycin C increased the frequency of gentamicin resistant SCVs, while other antibiotic classes failed to do so. The higher proportion of SCVs in cultures exposed to fluoroquinolones and mitomycin C compared to un-exposed cultures correlate with an increased mutation rate monitored by rifampicin resistance and followed induction of the SOS DNA damage response.ConclusionOur observations suggest that environmental stimuli, including antimicrobials that reduce replication fidelity, increase the formation of SCVs through activation of the SOS response and thereby potentially promote persistent infections that are difficult to treat.
Highlights
In Staphylococcus aureus sub-populations of slow-growing cells forming small colony variants (SCVs) are associated with persistent and recurrent infections that are difficult to eradicate with antibiotic therapies
When measuring the minimum inhibitory concentration (MIC) of the strains, increased susceptibility was evident for the lexA(S130A) mutant towards chloramphenicol, as well as the DNA targeting antimicrobials; ciprofloxacin, moxifloxacin and mitomycin C, while equal MIC between the two strains was observed for gentamicin, rifampicin and vancomycin (Table 1)
We measured the effect of sub-inhibitory concentrations (0.5 MIC) of antibiotics on the formation of gentamicin resistant SCVs using the wild type S. aureus strain 8235-4 and the isogenic lexA(S130A) mutant
Summary
In Staphylococcus aureus sub-populations of slow-growing cells forming small colony variants (SCVs) are associated with persistent and recurrent infections that are difficult to eradicate with antibiotic therapies. The emergence of slow-growing Staphylococcus aureus mutants, known as small colony variants (SCVs), is associated with sub-acute infections displaying enhanced intracellular residency in host cells promoting persistent and recurrent infections and an increased risk of antibiotic treatment failure [1]. Short-term enhanced mutation rates of bacterial cells can occur through activation of the SOS response [14] and activation of the SOS response could potentially increase the frequency of SCVs. The SOS regulon is generally repressed by LexA, but upon DNA damage it undergoes autocleavage in response to RecA binding to single-stranded DNA [15]. Inactivation of the LexA repressor leads to the expression of the SOS regulon This regulon includes genes involved in DNA repair, recombination, as well as error-prone polymerases [16]. We have investigated if antimicrobial compounds that interfere with DNA-, RNA-, protein- and cell wall synthesis affect the proportion of SCVs in the population
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