Three new fusidic acid derivatives and their antibacterial activity

Two steroid acids, cephalosporin P₁ and isocephalosporin P₁, were isolated from Hapsidospora irregularis FERM BP-2511. These compounds are structurally related to fusidic acid. Their NMR data were completely assigned on the basis of the 2D NMR spectra. Incubation of these two compounds with Microbacterium oxydans CGMCC 1788 in Luria-Bertani broth yielded the same set of three new 3-dehydrogenated products, 3-keto-isocephalosporin P₁, 3-keto-cephalosporin P₁ and 6-deacetyl-3-keto-cephalosporin P₁. The final pH of the bacterial culture was 9.0. Incubation of 3-keto-isocephalosporin P₁ or 3-keto-cephalosporin P₁ in Tris-HCl buffer (pH 9.0) revealed that these two compounds can convert to each other by shifting the acetyl group between C-6 and C-7. The acetyl group at C-6 or C-7 can also be removed by hydrolysis to yield the minor product 6-deacetyl-3-keto-cephalosporin P₁. These fusidic acid derivatives were tested for the antibacterial activity against the Gram-positive pathogen Staphylococcus aureus. 3-Keto-cephalosporin P₁ showed the highest activity among the five compounds, with a minimal inhibition concentration (MIC) of 4 μg/mL, which is more potent than the substrate cephalosporin P₁. Both cephalosporin P₁ and 3-keto-cephalosporin P₁ were active against methicillin-resistant S. aureus, with the same MIC of 8 μg/mL.