Insect peptides with improved protease-resistance protect mice against bacterial infection

At a time of the emergence of drug-resistant bacterial strains, the develop ment of antimicrobial compounds with novel mechanisms of action is of consi derable interest. Perhaps the most promising among these is a family of ant ibacterial peptides originally isolated from insects. These were shown to a ct in a stereospecific manner on an as-yet unidentified target bacterial pr otein. One of these peptides, drosocin, is inactive in vivo due to the rapi d decomposition in mammalian sera. However, another family member, pyrrhoco ricin, is significantly more stable, has increased in vitro efficacy agains t Gram-negative bacterial strains, and if administered alone, as we show he re, is devoid of in vitro or in vivo toxicity. At low doses, pyrrhocoricin protected mice against Escherichia call infection, but at a higher dose aug mented the infection of compromised animals. Analogs of pyrrhocoricin were, therefore, synthesized to further improve protease resistance and reduce t oxicity. A linear derivative containing unnatural amino acids at both termi ni showed high potency and lack of toxicity in vivo and an expanded cyclic analog displayed broad activity spectrum in vitro. The bioactive conformati on of native pyrrhocoricin was determined by nuclear magnetic resonance spe ctroscopy, and similar to drosocin, reverse turns were identified as pharma cologically important elements at the termini, bridged by an extended pepti de domain. Knowledge of the primary and secondary structural requirements f or in vivo activity of these peptides allows the design of novel antibacter ial drug leads.