Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins.
Beta-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 beta-lactam inhibition. Lactivicin (LTV; 1) contains separate cycloserine and gamma-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam. 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 gamma-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 beta-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.
Pauline
P
Macheboeuf
Delphine S
DS
Fischer
Tom
T
Brown
Astrid
A
Zervosen
André
A
Luxen
Bernard
B
Joris
Andréa
A
Dessen
Christopher J
CJ
Schofield
D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic; D011485:Protein Binding; D013296:Streptococcus pneumoniae / Q000737:chemistry
D046915:Penicillin-Binding Proteins; D010455:Peptides; D010456:Peptides, Cyclic; C051231:lactivicin