Complestatin Exerts Antibacterial Activity by the Inhibition of Fatty Acid Synthesis

Abstract

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 IC 50 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.

Generation of New Complestatin Analogues by Heterologous Expression of the Complestatin Biosynthetic Gene Cluster from Streptomyces chartreusis AN1542

“…[7] E. coli BW25113 carrying pIJ790 (John Innes Centre, Norwich, UK) was used for l-Red-mediated homologous recombination. [7] E. coli BW25113 carrying pIJ790 (John Innes Centre, Norwich, UK) was used for l-Red-mediated homologous recombination.…”

“…[7] The test strains were grown to the mid-log phase in Mueller-Hinton broth and diluted (1000-fold) in the same medium. [7] The test strains were grown to the mid-log phase in Mueller-Hinton broth and diluted (1000-fold) in the same medium.…”

“…[7] It exhibited antibacterial activity against S. aureus RN4220, methicillin-resistant S. aureus (S. aureus CCARM 3167 and S. aureus CCARM 3506), quinolone-resistant S. aureus (S. aureus CCARM3 505 and S. aureus CCARM 3519), and vancomycin-resistant Enterococcus VRE11a nd VRE7, with MICs of 8-16 mgmL À1 ;c omplestatin showedM ICs of 2-4 mgmL À1 (Table 1). [7] It exhibited antibacterial activity against S. aureus RN4220, methicillin-resistant S. aureus (S. aureus CCARM 3167 and S. aureus CCARM 3506), quinolone-resistant S. aureus (S. aureus CCARM3 505 and S. aureus CCARM 3519), and vancomycin-resistant Enterococcus VRE11a nd VRE7, with MICs of 8-16 mgmL À1 ;c omplestatin showedM ICs of 2-4 mgmL À1 (Table 1).…”

“…[4] Chloropeptin I, as tructurali somer of complestatin, was also isolated,a long with complestatin, from Streptomyces sp. [7] Interestingly,i ts antibacterial mechanism involves the inhibition of fatty-acid synthesis;t his differs from the antibacterial mechanism of vancomycin, thus indicating that complestatin has the potential to kill vancomycin-resistant pathogenic bacteria. [5] Complestatin analogues neuroprotectins Aa nd B, isolated from Streptomyces sp.…”

“…[6] Recently,w er eported the potent antibacterial activity of complestatin isolated from Streptomyces chartreusis AN1542:m inimum inhibitory concentration( MIC)o f 2 mgmL À1 against drug-resistantG ram-positive pathogens such as methicillin-resistant Staphylococcus aureus. [7] Interestingly,i ts antibacterial mechanism involves the inhibition of fatty-acid synthesis;t his differs from the antibacterial mechanism of vancomycin, thus indicating that complestatin has the potential to kill vancomycin-resistant pathogenic bacteria. However,t he exact mechanism of action at the molecular level is unknown.…”