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Discovery of new antibiotics for combating methicillin-resistant Staphylococcus aureus (MRSA) is of vital importance in the post-antibiotic era. Here, we report four avenaciolide derivatives (1-4) isolated from Neosartorya fischeri, three of which had significant antimicrobial activity against MRSA. The morphology of avenaciolide-treated cells was protoplast-like, which indicated that cell wall biosynthesis was interrupted. Comparing the structures and minimum inhibitory concentrations of 1-4, the α,β-unsaturated carbonyl group seems to be an indispensable moiety for antimicrobial activity. Based on a structural similarity survey of other inhibitors with the same moiety, we revealed that MurA was the drug target. This conclusion was validated by (31)P NMR spectroscopy and MS/MS analysis. Although fosfomycin, which is the only clinically used MurA-targeted antibiotic, is ineffective for treating bacteria harboring the catalytically important Cys-to-Asp mutation, avenaciolides 1 and 2 inhibited not only wild-type but also fosfomycin-resistant MurA in an unprecedented way. Molecular simulation revealed that 2 competitively perturbs the formation of the tetrahedral intermediate in MurA. Our findings demonstrated that 2 is a potent inhibitor of MRSA and fosfomycin-resistant MurA, laying the foundation for the development of new scaffolds for MurA-targeted antibiotics.

2'-Aldehydes and 2'-ketones of alpha-C-glycosides, including the gluco-, galacto-, and manno- series, were epimerized exclusively to their beta-anomers in good-to-excellent yields under basic conditions and in the presence of zinc acetate. The beta-stereoselectivity is independent of the neighboring group at 2-O-substitution of sugar substrates. Therefore, this provides a particularly useful method for the preparation of manno-beta-C-glycosides. The epimerization is likely initiated by the formation of Zn-enolate that is stabilized by intramolecular chelation to the pyranose ring-oxygen to form a syn chair-boat structure. Due to the activation generated by the Zn-O coordination, fission of the C1-O bond occurs, leading to opening of the pyranose ring, which is spontaneously followed by a change in conformation. The more stable anti chair-boat transition state is favored, and the subsequent hetero-intramolecular Michael addition results in the formation of beta-C-glycoside in a ring-closure step.