Highly active antibacterial ferrocenoylated or ruthenocenoylated Arg-Trp peptides can be discovered by an L-to-D substitution scan

The rapid increase in resistance against common antibiotics calls for the development of novel antibiotics, particularly against multi-resistant bacteria such as the methicillin-resistant Staphylococcus aureus (MRSA). In this work, the two group 8 metallocenoyl derivatives ferrocenoyl (FcC(O)-) or ruthenocenoyl (RcC(O)-) were attached to the N-terminus of two libraries of short antimicrobial peptides (AMPs), resulting in organometallic-AMP derivatives with as yet unparalleled antibacterial activities. In addition, these organometallic AMPs only cause limited lysis of human red blood cells (hRBCs). Our structure-activity relationship (SAR) study on these metallocenoylated peptides showed that specific combinations of L- and D-amino acid residues result in peptides with significantly improved antibacterial activity. Whereas the all-L FcC(O)-containing lead peptide had a MIC of 12 mu M against MRSA, several peptides were found with MIC-values as low as 1.5-3 mu M, a 4-8-fold increase in activity. For the RcC(O)-derivatized peptides a similar result was obtained: against MRSA a MIC value of 5.8 mu M for the all-L peptide could be lowered to 0.7 mu M, an 8-fold improvement. In addition, exposure of human red blood cells with 121 mu M of the most active peptides led to a maximum hemolysis of 6%, indicating prominent selectivity that can be used to realize antibiotics based on organometallic-AMPs. We have hereby performed a systematic and highly successful SAR optimization against the two crucial parameters, i.e. antibacterial activity and hemolysis. Importantly, some of the RcC(O)-derivatized peptides presented here are among the most active antibacterial peptides; they approach or even exceed the activity of vancomycin. c4sc01822b-f