Vinaxanthone, a new FabI inhibitor from Penicillium sp.
OBJECTIVE
Bacterial enoyl-ACP reductase (FabI) has been validated as a novel antibacterial target for tackling infections caused by multidrug-resistant pathogens. A few FabI inhibitors, however, are known. This study isolated a new FabI inhibitor from Penicillium sp.


METHODS
A screening programme led to the selection of a Penicillium sp. producing a strong FabI-inhibitory metabolite. The chemical structure of the isolated FabI inhibitor was elucidated by mass spectrometry and nuclear magnetic resonance spectral data. The antibacterial target of the inhibitor was validated by overexpression assays.


RESULTS
The isolated FabI inhibitor was elucidated to be vinaxanthone. It selectively inhibited Staphylococcus aureus FabI with an IC(50) of 0.9 microM; it did not affect FabK, an enoyl-ACP reductase of Streptococcus pneumoniae. Consistent with its inhibition of FabI, the inhibitor prevented intracellular fatty acid synthesis while it did not affect protein biosynthesis. It also prevented the growth of S. aureus as well as methicillin-resistant S. aureus (MRSA) and quinolone-resistant S. aureus. Importantly, fabI-overexpressing S. aureus showed reduced susceptibility to the inhibitor compared with the wild-type strain, demonstrating that its antibacterial action is mediated by inhibition of FabI.


CONCLUSIONS
Vinaxanthone is a new FabI-directed antibacterial of natural origin that could have potential for further development as a new anti-MRSA agent.
Zheng
Chang Ji
CJ
Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Korea.
Sohn
Mi-Jin
MJ
Kim
Won-Gon
WG
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010407:Penicillium / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D044004:Xanthones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D044004:Xanthones; C086647:vinaxanthone; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)