Enhancement by novel anti-methicillin-resistant Staphylococcus aureus compound HT61 of the activity of neomycin, gentamicin, mupirocin and chlorhexidine: in vitro and in vivo studies

Abstract

Previously, we described a small quinoline-derived compound that exhibited selective bactericidal activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). It depolarizes the bacterial cell membrane. In this study, we investigated if HT61 was able to enhance the potency of other antibiotics, namely neomycin, gentamicin and mupirocin, and an antiseptic, namely chlorhexidine, against clinical isolates of MSSA and MRSA in vitro and in vivo. The MICs were determined by the broth microdilution method. The effect of combinations was examined using the chequerboard method and time-kill curves. A murine skin infection model was used to evaluate the enhancement by HT61 of other antimicrobials. Using the fractional inhibitory concentration index, no interaction was seen in both MSSA and MRSA for the pair HT61 and gentamicin or the pair HT61 and neomycin. Synergism was seen for 65% of both MSSA and MRSA when HT61 was combined with chlorhexidine. There was also no interaction between HT61 and mupirocin. Time-kill analysis demonstrated significant synergistic activities when a low level of HT61 was combined with neomycin, gentamicin or chlorhexidine. The effect was more dramatic against non-multiplying bacteria against which the antimicrobials used were inactive on their own. Significant synergistic effects were also seen on mouse infected skin. We demonstrate that HT61, developed as a topical agent, acts as an enhancer that accelerates the activities of other antimicrobial agents against both MSSA and MRSA.