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<p>Keratinicyclins and keratinimicins are recently discovered glycopeptide antibiotics (GPAs). The latter are canonical
GPAs with broad-spectrum activity against Gram-positive bacteria, while keratinicyclins form a new chemotype by virtue of an
unusual oxazolidinone moiety and exhibit specific antibiosis against Clostridium difficile. Here, we investigated the three-dimensional
structures and functional consequences for both molecules. Equilibrium binding studies showed tight binding by keratinimicin A, but
not keratinicyclin B, to the peptidoglycan terminus. Using protein crystallography methods, we solved the X-ray crystal structures of
both GPAs, which, in conjunction with DFT calculations, indicate that the inability of keratinicyclin B to bind the peptidoglycan is
governed by steric factors. Keratinicyclin B, therefore, interferes with an alternative target to inhibit C. difficile growth, a conclusion
confirmed by checkerboard analysis that revealed synergistic activity with vancomycin. Our results set the stage for identifying the
molecular target of keratinicyclins and for exploring their therapeutic utility in combination with vancomycin.
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Robust topological phase in proximitized core–shell nanowires coupled to multiple superconductors
