Efficacy of newly generated short antimicrobial cationic lipopeptides against methicillin-resistant Staphylococcus aureus (MRSA)

ABSTRACT Infection caused by methicillin-resistant Staphylococcus aureus (MRSA) is a serious clinical challenge and research to develop new antimicrobials is imperative. In our study, we investigated the in vitro and in vivo efficacy of the short cationic dialkyl lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2. The antibacterial efficacy of (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 were evaluated in representative clinical methicillin-susceptible and resistant S. aureus strains by both in vitro [minimal inhibitory concentration (MIC), time-kill curve] and in vivo (wax worms model) approaches. These studies revealed that both (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 have rapid bactericidal activity, with a decrease of more than 3 log10 colony forming units (CFU)/mL achieved in the first 6 h of treatment. Furthermore, (C10)2-KKKK-NH2 performed similarly to daptomycin with a sustained bacterial killing after 24h. Wax worms infected and treated with these lipopeptides showed a decreased survival rate of 90-50% within the first day of treatment. We determined by Scanning Electron Microscopy that the effect of the short lipopeptides in S. aureus was associated with important morphological structural changes that may suggest cell membrane perturbation. In conclusion, our findings suggest that the short lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 may be potential new options for the treatment of MRSA infection.