Complestatin Exerts Antibacterial Activity by the Inhibition of Fatty Acid Synthesis

• Published in: Biological & pharmaceutical bulletin 2015/05/01, Vol.38(5), pp.715-721
• Main Authors: Kwon, Yun-Ju, Kim, Hyun-Ju, Kim, Won-Gon
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; antibacterial; Chlorophenols - pharmacology; Chlorophenols - therapeutic use; complestatin; Drug Resistance - drug effects; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors; enoyl-acyl carrier protein reductase; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; fatty acid synthesis; Fatty Acids - biosynthesis; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - growth & development; Methicillin-Resistant Staphylococcus aureus - metabolism; Microbial Sensitivity Tests; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Peptides, Cyclic - pharmacology; Peptides, Cyclic - therapeutic use; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - growth & development; Staphylococcus aureus - metabolism; Streptomyces; Streptomyces - metabolism
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b14-00824

Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of Staphylococcus aureus enoyl-ACP reductase (FabI), complestatin was isolated as a potent inhibitor of S. aureus FabI together with neuroprotectin A and chloropeptin I from Streptomyces chartreusis AN1542. Complestatin and related compounds inhibited S. aureus FabI with IC50 of 0.3–0.6 µM. They also prevented the growth of S. aureus as well as methicillin-resistance S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA), with minimum inhibitory concentrations (MICs) of 2–4 µg/mL. Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in S. aureus, whereas it did not affect the macromolecular biosynthesis of other cellular components, such as DNA, RNA, proteins, and the cell wall. Additionally, supplementation with exogenous fatty acids reversed the antibacterial effect of complestatin, demonstrating that it targets fatty acid synthesis. In this study, we reported that complestatin and related compounds showed potent antibacterial activity via inhibiting fatty acid synthesis.