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

Introduction: Infection caused by methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) is a serious clinical challenge and research to develop new antimicrobials is imperative.

Methods: This study investigated the in vitro and in vivo efficacy of the short cationic dialkyl lipopeptides (C)-KKKK-NH and (C)-KKKK-NH. The antibacterial efficacy of (C)-KKKK-NH and (C)-KKKK-NH was evaluated in representative clinical methicillin-susceptible S. aureus and MRSA strains by both in vitro (MIC, time-kill curve) and in vivo (wax worms model) approaches.

Results: These studies revealed that both (C)-KKKK-NH and (C)-KKKK-NH have rapid bactericidal activity, with a decrease of > 3 log colony forming units (CFU)/mL achieved in the first 6 hours of treatment. Furthermore, (C)-KKKK-NH performed similarly to daptomycin, with a sustained bacterial killing after 24 hours. Wax worms infected and treated with these lipopeptides showed a decreased survival rate of 90% to 50% within the first day of treatment. Scanning electron microscopy determined that the effect of the short lipopeptides in S. aureus was associated with important morphological structural changes that may suggest cell membrane perturbation.

Conclusion: These findings suggest that the short lipopeptides (C)-KKKK-NH and (C)-KKKK-NH may be potential new options for treating MRSA infections.