Peptide inhibitors of MurD and MurE, essential enzymes of bacterial cell wall biosynthesis

Continuous development of antibacterial compounds with novel modes of action (accompanied by rationalization of chemotherapeutic prescription) is the best way to address the growing problem of antibiotic-resistant infections. Numerous clinically important antibiotics interfere with peptidoglycan cell wall biosynthesis making this unique metabolic pathway a well validated target for antimicrobials. While nearly all of these antibiotics inhibit late stages of murein synthesis occurring on the extracellular side of plasma membrane, initial cytoplasmic steps have not been extensively exploited as drug targets. We performed affinity selection of peptides from phage-displayed libraries against two essential bacterial enzymes MurD and MurE involved in the cytoplasmic synthesis of peptidoglycan monomer. Selected peptides were found to inhibit respective target enzymes in an in vitro assay with IC(50) values of 140 microM to 1.5 mM. These peptides represent starting point for design of peptidomimetic lead compounds with the ultimate objective of small molecule chemotherapeutic development.