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Peptide inhibitors of MurD and MurE, essential enzymes of bacterial cell wall biosynthesis
Bratkovič, Tomaž, farmacevt, 1978- ...
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 targetfor 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-displayedlibraries against two essential bacterial enzymes MurD and MurEinvolved in the cytoplasmic synthesis of peptidoglycan monomer. Selected peptides were found to inhibit respective target enzymes in an in vitro assay with IC50 values of 140 M to 1.5 mM. These peptides represent starting point for design of peptidomimetic lead compounds with the ultimate objective of small molecule chemotherapeutic development.
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