Design and Synthesis of Peptidic Natural Product Analogues as Anti-infective Drug Leads

Abstract

Natural products, including peptides, offer a rich source of bioactive metabolites commonly exploited for the development of drug therapies. Accordingly, our research endeavors have been inspired by two peptidic natural products, gallinamide A and glycinocin A, B & C. Isolated from marine cyanobacteria of the genus Schizothrix, gallinamide A is a depsipeptide natural product. Gallinamide A possesses antimalarial activity against chloroquine-resistant Plasmodium falciparum, the etiological agent of malaria, while exhibiting low cytotoxicity against human cell lines. Previous work has demonstrated that gallinamide A exhibits antimalarial activity through the inhibition of cysteine protease enzymes in P. falciparum responsible for the degradation of host hemoglobin. This work has provided an opportunity to design and synthesize novel antimalarial drug leads, based on the gallinamide A scaffold, that operate by a novel mode of action to current therapies for which significant resistance has emerged. Glycinocin A-C are a calcium dependent lipopeptide class of natural products isolated from Streptomyces viridochromogenes. Glycinocin A possesses antibiotic activity against a range of Gram-positive bacteria, including vancomycin and methicillin resistant Staphylococcus aureus. By binding to undecaprenyl phosphate, an essential cell wall lipid precursor, glycinocin A disrupts bacterial outer membrane formation, a process promoted by an increase of extracellular Ca2+ concentration. These biological properties motivated us to investigate glycinocin A-C and their associated antibiotic activity. Through the synthesis of glycinocin A-C and related structural analogues, critical structure-activity relationship trends have been established. Through their novel mode of action and interesting bioactivity, glycinocin analogues offer promising potential as novel antibiotic drug leads.