Conversion of a Short Lipopeptoid into Longer Non-lipidated Repeat Peptoids with Improved Activity

Abstract

The need for new antibiotics to treat antibiotic resistant bacteria has been a growing problem worldwide over the past several years. Bacteria are quickly developing modifications to render antibiotics useless due to overuse and misuse of medications. With the need for new classes of antibiotics, developing peptoids as potential antibiotics to treat nosocomial pathogens is the overarching goal of this research project. The ESKAPE bacteria are the focus of this research because of their well characterized global health risk. A series of monomer sequence repeat peptoids, termed the MNT series, were designed from a previously discovered lipopeptoid, termed ALA1. This was done in an effort to determine the peptoid length requirement when converting a short lipopeptoid into a longer non-lipidated peptoid. It was hypothesized that removing the lipid tail would reduce toxicity while lengthening the peptoid would allow for retention of antibacterial activity. A total of four MNT series peptoids (MNT1, MNT2, MNT3, and MNT4) ranging from 3 to 12 monomers in length without a lipid tail were synthesized and characterized for antibacterial efficacy and mammalian cytotoxicity. This research determined that MNT3, which is 9 monomers in length, was the most promising ALA1 derivative. This compound was more potent towards gram-positive pathogens, such as E. faecium, E. faecalis, and S. aureus than ALA1 or the longer MNT4 peptoid. In general, all non-lipidated MNT series peptoids were less effective against gram-negative bacteria than ALA1. Cytotoxicity testing of the MNT series peptoids and ALA1 against HepG2 liver cells and red blood cells indicated that MNT3 had lower cytotoxicity than ALA1 or MNT4. The shortest derivatives, MNT1 and MNT2 displayed no antibacterial activity or cytotoxicity, demonstrating the dependence of peptoid length or lipidation for both of these parameters.