title: Meleagrin, a new FabI inhibitor from Penicillium chryosogenum with at least one additional mode of action.
abstract: 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.
authors: Superbacteria Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea.
authors: Chang Ji
authors: CJ
authors: Zheng
authors: Mi-Jin
authors: MJ
authors: Sohn
authors: Sangku
authors: S
authors: Lee
authors: Won-Gon
authors: WG
authors: Kim
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D053898:Biosynthetic Pathways / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial / Q000235:genetics; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis; D015870:Gene Expression; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010059:Ovomucin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010408:Penicillium chrysogenum / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D010059:Ovomucin; C060672:meleagrin; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)