cyslabdan and spirohexaline

Methicillin-resistant Staphylococcus aureus (MRSA) is known as a major nosocomial pathogen that has also developed resistance to many antibiotics. Moreover, MRSA resistance to a last-resort antibiotic, vancomycin, has been reported. Therefore, new anti-infectious agents to prevent and treat MRSA infection are needed. Based on this background, our group has focused on the discovery of new microbial agents active against MRSA infection. Viridicatumtoxin and spirohexaline, produced by Penicillium sp. FKI-3368, were isolated as inhibitors of undecaprenyl pyrophosphate (UPP) synthase of Staphylococcus aureus, which was involved in cell wall synthesis. Viridicatumtoxin and spirohexaline with a pentacyclic spiro skeleton inhibited UPP synthase activity with an IC(50) value of 4.0 and 9.0 µM, respectively. Actually, the growth of gram-positive bacteria including MRSA was strongly inhibited by the compounds. Our computational modeling experiments indicated that spirohexaline A was inserted into the substrate pocket of UPP synthase and interacted with Glu(88) via a carbamoyl group of the compound, with Ala(76), Met(54) and Asn(35) via three hydroxyl groups, and with certain hydrophobic amino acids via a spiro ring. Cyslabdan, produced by Streptomyces sp. K04-0144, was isolated as a potentiator of β-lactam imipenem activity against MRSA. The compound consisted of a labdan skeleton and an N-acetylcysteine. Cyslabdan potentiated imipenem activity by over 1000 fold, drastically reducing the MIC value of imipenem against MRSA from 16 to 0.03 µg/mL. The binding proteins of cyslabdan were investigated in the lysate of MRSA to identify FemA, which was involved in the formation of the pentaglycine interpeptide bridge in MRSA peptidoglycan.

Topics: Acetylcysteine; Alkyl and Aryl Transferases; Anti-Bacterial Agents; Cross Infection; Diterpenes; Drug Design; Drug Resistance, Bacterial; Drug Synergism; Imipenem; Methicillin-Resistant Staphylococcus aureus; Mycotoxins; Spiro Compounds

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.

Topics: Acetylcysteine; Alkyl and Aryl Transferases; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactams; Cell Wall; Diterpenes; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mycotoxins; Organothiophosphorus Compounds; Peptidoglycan; Spiro Compounds; Teichoic Acids; Vancomycin; Virulence Factors; Xanthophylls