Abstract
Clinically useful antibiotics, β-lactams and vancomycin, are known to inhibit bacterial cell wall peptidoglycan synthesis. Methicillin-resistant Staphylococcus aureus (MRSA) has a unique cell wall structure consisting of peptidoglycan and wall teichoic acid. In recent years, new anti-infectious agents (spirohexaline, tripropeptin C, DMPI, CDFI, cyslabdan, 1835F03, and BPH-652) targeting MRSA cell wall biosynthesis have been discovered using unique screening methods. These agents were found to inhibit important enzymes involved in cell wall biosynthesis such as undecaprenyl pyrophosphate (UPP) synthase, FemA, flippase, or UPP phosphatase. In this review, the discovery, the mechanism of action, and the future of these anti-infectious agents are described.
Highlights
Peptidoglycan, the major component of the bacterial cell wall, is an attractive target for the development of anti-infectious agents
undecaprenyl pyrophosphate (UPP) synthase is expected to be an attractive target for the development of anti-infectious agents that are effective against resistant bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE)
Direct binding of tripropeptin C to UPP was observed by analyses of mass spectrometry and thin-layer chromatography, suggesting that tripropeptin C inhibits UPP phosphatase activity, which is involved in the lipid cycle of peptidoglycan synthesis
Summary
Peptidoglycan, the major component of the bacterial cell wall, is an attractive target for the development of anti-infectious agents. The transglycosylation and transpeptidation between a pentaglycyl murein monomer and an oligomeric peptidoglycan intermediate take place on the external surface of the membrane in a sequential reaction catalyzed by penicillin-binding proteins (PBPs); MurNAc of murein monomers is connected to GlcNAc by PBP transglycosylase to extend the glycan chains, and the terminal Gly of the pentaglycine of murein monomers is connected to the second D-Ala of the pentapeptide with the concomitant release of the terminal D-Ala by PBP transpeptidase to form crosslinks between murein monomers. Several compounds have been found to have new mechanisms of action against MRSA and are expected to be potential leads for the treatment of infection They include microbial natural products like spirohexaline, tripropeptin C, and cyslabdan; and synthetic compounds such as DMPI, CDFI, 1835F03, targocil, and BPH-652. These compounds target peptidoglycan, wall teichoic acid, and a virulence factor of S. aureus. The discovery, biological activity, and mechanisms of action of these compounds are described
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