Abstract
β-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid β-lactam inhibition1. Lactivicin (LTV; 1) contains separate cycloserine and γ-lactone rings and is the only known natural PBP inhibitor that does not contain a β-lactam2,3,4. Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and γ-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against β-lactam–resistant bacteria.
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Acknowledgements
We thank the ESRF ID14 and ID23 beamline staff for help with data collection, D. Lemaire (IBS) for mass spectrometric assays, J. Croizé (Hopital Universitaire de Grenoble) for drug-resistant pneumococcal strains, R. Carapito for the purification of PBP2x (5204) and O. Dideberg for support. We thank J.M. Frère (ULG) for useful discussions. The work was funded by the European Commission LSHM-CT-2004-512138 (EUR-INTAFAR).
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P.M. and A.D. carried out the crystallographic analyses; D.S.F. and T.B. Jr. carried out the synthetic studies; A.Z., A.L., P.M. and B.J. carried out microbiological and kinetic analyses; A.D., D.S.F. and C.J.S. designed the study, analyzed data and, together with the other authors, wrote the paper. All authors discussed the results and commented on the manuscript.
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Macheboeuf, P., Fischer, D., Brown, T. et al. Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. Nat Chem Biol 3, 565–569 (2007). https://doi.org/10.1038/nchembio.2007.21
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DOI: https://doi.org/10.1038/nchembio.2007.21
