The nonantibiotic small molecule cyslabdan enhances the potency of β-lactams against MRSA by inhibiting pentaglycine interpeptide bridge synthesis

The nonantibiotic small molecule cyslabdan, a labdan-type diterpene produced by Streptomyces sp. K04-0144, markedly potentiated the activity of the β-lactam drug imipenem against methicillin-resistant Staphylococcus aureus (MRSA). To study the mechanism of action of cyslabdan, the proteins that bind...

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Published in:PloS one 2012, Vol.7 (11), p.e48981
Main Authors: Koyama, Nobuhiro, Tokura, Yuriko, Münch, Daniela, Sahl, Hans-Georg, Schneider, Tanja, Shibagaki, Yoshio, Ikeda, Haruo, Tomoda, Hiroshi
Format: Article
Language:English
Subjects:
Acetylcysteine - analogs & derivatives
Acetylcysteine - pharmacology
Amides
Antibiotics
Antimicrobial agents
Bacterial Proteins - antagonists & inhibitors
Biology
Boron Compounds
Cell walls
Chemical synthesis
Chemistry
Chromatography, High Pressure Liquid
Diterpenes - pharmacology
DNA Primers - genetics
Drug resistance
Drug Resistance, Bacterial - genetics
Drug Synergism
Imipenem
Imipenem - pharmacology
Japan
Lipids
Medicine
Methicillin
Methicillin-Resistant Staphylococcus aureus - drug effects
Methicillin-Resistant Staphylococcus aureus - metabolism
Monomers
Penicillin
Penicillins
Pentaglycine
Peptides - metabolism
Peptidoglycan - metabolism
Peptidoglycans
Pharmaceutical sciences
Protein biosynthesis
Proteins
Solvents
Spectrophotometry, Ultraviolet
Staphylococcus aureus
Staphylococcus infections
Streptomyces
Tandem Mass Spectrometry
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cited_by cdi_FETCH-LOGICAL-c526t-668b330372d05460e9bce19d52e7b7471451c7483f0d2f67f12ee2d6fc56bbac3
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container_end_page
container_issue 11
container_start_page e48981
container_title PloS one
container_volume 7
creator Koyama, Nobuhiro
Tokura, Yuriko
Münch, Daniela
Sahl, Hans-Georg
Schneider, Tanja
Shibagaki, Yoshio
Ikeda, Haruo
Tomoda, Hiroshi
description The nonantibiotic small molecule cyslabdan, a labdan-type diterpene produced by Streptomyces sp. K04-0144, markedly potentiated the activity of the β-lactam drug imipenem against methicillin-resistant Staphylococcus aureus (MRSA). To study the mechanism of action of cyslabdan, the proteins that bind to cyslabdan were investigated in an MRSA lysate, which led to the identification of FemA, which is involved in the synthesis of the pentaglycine interpeptide bridge of the peptidoglycan of MRSA. Furthermore, binding assay of cyslabdan to FemB and FemX with the function similar to FemA revealed that cyslabdan had an affinity for FemB but not FemX. In an enzyme-based assay, cyslabdan inhibited FemA activity, where as did not affected FemX and FemB activities. Nonglycyl and monoglycyl murein monomers were accumulated by cyslabdan in the peptidoglycan of MRSA cell walls. These findings indicated that cyslabdan primarily inhibits FemA, thereby suppressing pentaglycine interpeptide bridge synthesis. This protein is a key factor in the determination of β-lactam resistance in MRSA, and our findings provide a new strategy for combating MRSA.
doi_str_mv 10.1371/journal.pone.0048981
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subjects Acetylcysteine - analogs & derivatives
Acetylcysteine - pharmacology
Amides
Antibiotics
Antimicrobial agents
Bacterial Proteins - antagonists & inhibitors
Biology
Boron Compounds
Cell walls
Chemical synthesis
Chemistry
Chromatography, High Pressure Liquid
Diterpenes - pharmacology
DNA Primers - genetics
Drug resistance
Drug Resistance, Bacterial - genetics
Drug Synergism
Imipenem
Imipenem - pharmacology
Japan
Lipids
Medicine
Methicillin
Methicillin-Resistant Staphylococcus aureus - drug effects
Methicillin-Resistant Staphylococcus aureus - metabolism
Monomers
Penicillin
Penicillins
Pentaglycine
Peptides - metabolism
Peptidoglycan - metabolism
Peptidoglycans
Pharmaceutical sciences
Protein biosynthesis
Proteins
Solvents
Spectrophotometry, Ultraviolet
Staphylococcus aureus
Staphylococcus infections
Streptomyces
Tandem Mass Spectrometry
title The nonantibiotic small molecule cyslabdan enhances the potency of β-lactams against MRSA by inhibiting pentaglycine interpeptide bridge synthesis
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