Abstract
Rifamycin W, the most predominant intermediate in the biosynthesis of rifamycin, needs to undergo polyketide backbone rearrangement to produce rifamycin B via an oxidative cleavage of the C-12/C-29 double bond. However, the mechanism of this putative oxidative cleavage has not been characterized yet. Rif-Orf5 (a putative cytochrome P450 monooxygenase) was proposed to be involved in the cleavage of this olefinic moiety of rifamycin W. In this study, the mutant strain Amycolatopsis mediterranei S699 Δrif-orf5 was constructed by in-frame deleting the rif-orf5 gene to afford thirteen rifamycin W congeners (1–13) including seven new ones (1–7). Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data and high-resolution ESI mass spectra. Presumably, compounds 1–4 were derivatized from rifamycin W via C-5/C-11 retro-Claisen cleavage, and compounds 1–3, 9 and 10 featured a hemiacetal. Compounds 5–7 and 11 showed oxygenations at various sites of the ansa chain. In addition, compounds 1–3 exhibited antibacterial activity against Staphylococcus aureus with minimal inhibitory concentration (MIC) values of 5, 40 and 0.5 µg/mL, respectively. Compounds 1 and 3 showed modest antiproliferative activity against HeLa and Caco-2 cells with half maximal inhibitory concentration (IC50) values of about 50 µM.
Highlights
Ansamycins are a family of macrolactam antibiotics that are synthesized by type I polyketide synthase (PKS), which are structurally characterized by an aromatic moiety bridged at nonadjacent positions by an aliphatic chain [1,2]
As the representative members of the ansamycin family, rifamycins were first isolated from Amycolatopsis mediterranei S699 in 1957 [3,4,5]
The results showed that new compounds 1–3 and known compounds 11 and 13 exhibited inhibitory activity against S. aureus ATCC 25923, while other compounds showed no antimicrobial activity (Figure S56)
Summary
Ansamycins are a family of macrolactam antibiotics that are synthesized by type I polyketide synthase (PKS), which are structurally characterized by an aromatic moiety bridged at nonadjacent positions by an aliphatic chain (ansa chain) [1,2]. As the representative members of the ansamycin family, rifamycins were first isolated from Amycolatopsis mediterranei S699 in 1957 [3,4,5]. Mycobacterium tuberculosis has developed significantly increased resistance to rifamycin antibiotics due to their extensive clinical use during recent decades [10,11]. The biosynthesis of rifamycins has been continuously studied since the 1980s, which can be divided into three stages. During the first two stages, the biosynthesis of start unit
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