Staphylococcus aureus asymptomatically colonizes the anterior nares of humans but also causes a wide spectrum of acute and chronic diseases. The ability of S. aureus to cause such a wide variety of diseases is probably due to the fact that it produces a large number of cell-bound and secreted virulence factors (15). Much of the dissimilarity between S. aureus strains is dependent on the presence of mobile genetic elements, such as plasmids, bacteriophages, pathogenicity islands, transposons, and insertions sequences (2, 9, 13). Many virulence factors are encoded on such mobile elements (3,5,12,18,19,26). Phages which integrate into the chromosomal gene coding for -hemolysin (hlb) are widely distributed in S. aureus strains of human origin. Most of them encode accessory virulence determinants such as staphylokinase (sak) and enterotoxins (5, 10). Staphylokinase is a plasminogen activator and has thus been postulated to aid the bacteria in their dissemination from clots and abscesses (1). Additionally, it was shown that S. aureus can resist human defensins by the production of staphylokinase (11).Many prophages are induced by environmental conditions that lead to DNA damage, including exposure to reactive oxygen species generated by leukocytes or exposure to exogenous agents such as antibiotics (24). We could show that phages are mobilized during chronic infection of the lungs of patients with cystic fibrosis (CF), possibly due to the strong selective pressure exercised on the pathogen by the specific host response and/or by the regular exposure to antibiotics (8). Quinolones (for instance, ciprofloxacin) or trimethoprim are frequently used for the treatment of lung infections in patients with CF. Ciprofloxacin acts as an antibacterial agent by trapping DNA gyrase on DNA and thus blocking the replication fork movement. Trimethoprim prevents the incorporation of thymine into bacterial DNA by inhibiting the dihydrofolate reductase. Blockage of the replication fork by these drugs may trigger the DNA repair system. For Escherichia coli it was shown that damaged bacterial DNA interacts with and activates the multifunctional RecA protein (25). Stimulated RecA promotes the autoproteolysis of the repressor of DNA repair functions, LexA, and also that of the phage repressor CI (20, 25). The decline in active CI levels permits derepression of phage lytic genes and the resumption of lytic growth.We analyzed the effects of subinhibitory concentrations of ciprofloxacin and trimethoprim on phage induction and the expression of phage-related virulence factors in comparison to those of the classical phage-inducing agent mitomycin C in S. aureus. CF isolates for which induction of hlb-converting phages has been demonstrated in vivo (8) as well as a phage 13 lysogen of prototypic S. aureus strain 8325-4 were selected for this study. We showed that ciprofloxacin and trimethoprim trigger phage induction and lead to enhanced expression of phage-encoded virulence factors. MATERIALS AND METHODSBacterial strains. S. aureus isolates from...
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