Pleiotropic Anti-Infective Effects of Defensin-Derived Antimicrobial Compounds.

We identified low-molecular weight compounds derived from the antimicrobial peptide human neutrophil peptide-1 that bind to Lipid II, an essential precursor of bacterial cell wall biosynthesis. These compounds act as antibacterials on multiple biosynthesis pathways with specificity against gram-positive organisms. Here, we have tested a small subset of our most promising leads against the bacterium Clostridium perfringens and sporozoites of Eimeria tenella , an intracellular protozoan parasite that causes intestinal disease in poultry. We found one compound, 1611-0203 (2-{2,3,5,6-tetrafluoro-4-[2,3,5,6-tetrafluoro-4-(2-hydroxyphenoxy)phenyl]phenoxy}phenol), specifically to inhibit growth of both agents out of all compounds tested. Additionally, compound 1611-0203 inhibits Staphylococcus aureus and Enterococcus spp. Mechanism-of-action studies further reveal that 1611-0203 affects cell wall biosynthesis and inhibits additional biosynthetic pathways. Combined, our results indicate that compounds such as 1611-0203 have therapeutic potential to act as anti-infectives against various organisms simultaneously.