Meleagrin, a new FabI inhibitor from Penicillium chryosogenum with at least one additional mode of action

• Published in: PloS one Vol. 8; no. 11; p. e78922
• Main Authors: Zheng, Chang Ji, Sohn, Mi-Jin, Lee, Sangku, Kim, Won-Gon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.11.2013; Public Library of Science (PLoS)
• Subjects: Acyl carrier protein; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - pharmacology; Antibiotics; Antimicrobial agents; Aqueous solutions; Bacteria; Bacterial Proteins - antagonists & inhibitors; Binding sites; Biosynthesis; Biosynthetic Pathways - drug effects; Biotechnology; Chemotherapy; Chromatography; Derivatives; Drug Evaluation, Preclinical; Drug Resistance, Bacterial - genetics; E coli; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - genetics; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli - genetics; Fatty acids; Fatty Acids - biosynthesis; Fluorescence; Gene Expression; Inhibitors; Library collections; Magnetic resonance; Mammals; Mass spectroscopy; Microbial Sensitivity Tests; Microorganisms; Minimum inhibitory concentration; Mode of action; Multidrug resistance; Mutation; Natural products; NMR; Nuclear magnetic resonance; Ovomucin - chemistry; Ovomucin - isolation & purification; Ovomucin - pharmacology; Penicillium; Penicillium chrysogenum; Penicillium chrysogenum - metabolism; Proteins; Pseudomonas aeruginosa; Quenching; Reductase; Resistant mutant; Spectroscopy; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Staphylococcus aureus - genetics; Staphylococcus infections; Streptococcus infections; Triclosan; Tuberculosis; South Korea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0078922

Bacterial enoyl-acyl carrier protein reductase (FabI) is a promising novel antibacterial target. We isolated a new class of FabI inhibitor from Penicillium chrysogenum, which produces various antibiotics, the mechanisms of some of them are unknown. The isolated FabI inhibitor was determined to be meleagrin by mass spectroscopy and nuclear magnetic resonance spectral analyses, and its more active and inactive derivatives were chemically prepared. Consistent with their selective inhibition of Staphylococcus aureus FabI, meleagrin and its more active derivatives directly bound to S. aureus FabI in a fluorescence quenching assay, inhibited intracellular fatty acid biosynthesis and growth of S. aureus, and increased the minimum inhibitory concentration for fabI-overexpressing S. aureus. The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform. Additionally no resistant mutant to the compounds was obtained. Importantly, fabK-overexpressing Escherichia coli was not resistant to these compounds, but was resistant to triclosan. These results demonstrate that the compounds inhibited another target in addition to FabI. Thus, meleagrin is a new class of FabI inhibitor with at least one additional mode of action that could have potential for treating multidrug-resistant bacteria.