Abstract
Proansamycin X, a hypothetical earliest macrocyclic precursor in the biosynthesis of rifamycin, had never been isolated and identified. According to bioinformatics analysis, it was proposed that RifT (a putative NADH-dependent dehydrogenase) may be a candidate target responsible for the dehydrogenation of proansamycin X. In this study, the mutant strain Amycolatopsis mediterranei S699 ΔrifT was constructed by deleting the rifT gene. From this strain, eleven 8-deoxy-rifamycin derivatives (1–11) and seven known analogues (12–18) were isolated. Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data and high-resolution ESI mass spectra. Compound 1 is a novel amide N-glycoside of seco-rifamycin. Compounds 2 and 3 feature conserved 11,12-seco-rifamycin W skeleton. The diverse post-modifications in the polyketide chain led to the production of 4–11. Compounds 2, 3, 5, 6, 13 and 15 exhibited antibacterial activity against Staphylococcus aureus (MIC (minimal inhibitory concentration) values of 10, 20, 20, 20, 40 and 20 μg/mL, respectively). Compounds 14, 15, 16, 17 and 18 showed potent antiproliferative activity against KG1 cells with IC50 (half maximal inhibitory concentration) values of 14.91, 44.78, 2.16, 18.67 and 8.07 μM, respectively.
Highlights
Ansamycins are a type of macrocyclic antibiotics formed by an aromatic moiety bridged at nonadjacent positions by an aliphatic chain [1,2], and exemplified by the antituberculosis rifamycin [3], antitumor maytansine [4,5] and the Hsp90 inhibitor geldanamycin [6]
The semi-synthetic rifamycin derivatives such as rifampicin are clinically used for the treatment of tuberculosis, adhesion and leprosy infection caused by Staphylococcus and other G+ bacteria [12,13]
After analysis of the fermentation products cultivated for 7 days on ISP2 agar media at 28 ◦C by high-pressure liquid chromatography (HPLC) and LC-ESI-HRMS, the ∆rifT mutant exhibited a completely different metabolic profile from that of the wild-type strain (Figure 2)
Summary
Ansamycins are a type of macrocyclic antibiotics formed by an aromatic moiety bridged at nonadjacent positions by an aliphatic chain [1,2], and exemplified by the antituberculosis rifamycin [3], antitumor maytansine [4,5] and the Hsp inhibitor geldanamycin [6]. These macrolactams are constructed by the multidomain modular type I PKSs (polyketide synthases) using 3-amino-5-hydroxybenzoic acid (AHBA) as the starter unit [7], followed by various post-PKS modifications. In order to increase the structural diversity of rifamycins, the mechanism of rifamycin biosynthesis has been continuously studied [16,17,18]
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