OH radical production stimulated by (RW)4D, a synthetic antimicrobial agent and indolicidin

Antimicrobial peptides (AMPs) have been widely studied as a potential class of antibiotics for treating infectious diseases caused by multidrug-resistant (MDR) bacterial strains. While the cell surface and membrane are generally implicated in the antibacterial action of AMPs, we still lack a complete understanding of the detailed mechanism(s) involved. Here we show that the natural antimicrobial peptide indolicidin (ILN) and a more potent synthetic dendrimeric analog, (RW)(4D), generate hydroxide radicals in target bacterial cells via a Fenton reaction, as Collins group has reported for bactericidal antibiotics. Our results further suggest that the TCA cycle does not regulate release of irons from iron clusters, and electron donors such as NADH from the TCA cycle are only partially responsible for superoxide generation. Since AMP's are refractory to bacterial resistance, unlike the bacteriocidal antibiotics tested, we hypothesize that the source of the OH radicals differs from that in the latter case.