Avenaciolides: Potential MurA-Targeted Inhibitors Against Peptidoglycan Biosynthesis in Methicillin-Resistant Staphylococcus aureus (MRSA)

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 31P 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.