Letter abstract
Nature Chemical Biology 3, 565 - 569 (2007)
Published online: 5 August 2007 | doi:10.1038/nchembio.2007.21
Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins
Pauline Macheboeuf1,5, Delphine S Fischer2,5, Tom Brown, Jr2, Astrid Zervosen3, André Luxen3, Bernard Joris4, Andréa Dessen1 & Christopher J Schofield2
-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 -lactam inhibition1. Lactivicin (LTV; 1) contains separate cycloserine and 
-lactone rings and is the only known natural PBP inhibitor that does not contain a 
-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 
-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 -lactam–resistant bacteria.
- Institut de Biologie Structurale Jean-Pierre Ebel Commissariat à l'énergie atomique — Centre National de La Recherche Scientifique – Université Joseph Fourier, 41 rue Jules Horowitz, F-38027 Grenoble, France.
- Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
- Centre de Recherches du Cyclotron, B30, Université de Liège, Sart-Tilman, B-4000, Liège, Belgium.
- Centre d'Ingénierie des Protéines, Institut de Chimie, B6a, Université de Liège, Sart-Tilman, B-4000, Liège, Belgium.
- These authors contributed equally to this work.
Correspondence to: Andréa Dessen1 e-mail: andrea.dessen@ibs.fr
Correspondence to: Christopher J Schofield2 e-mail: christopher.schofield@chem.ox.ac.uk
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