2JCH

Structural and mechanistic basis of penicillin binding protein inhibition by lactivicins

Summary for 2JCH

• Entry DOI: 10.2210/pdb2jch/pdb
• Related: 2BG1 2BG3 2BG4 2FFF 2JCI
• Descriptor: PENICILLIN-BINDING PROTEIN 1B, SULFATE ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: peptidoglycan synthesis multifunctional enzyme, cell wall, peptidoglycan, gamma lactam antibiotics, binding protein, drug-binding protein
• Biological source: STREPTOCOCCUS PNEUMONIAE
• Total number of polymer chains: 1
• Total formula weight: 79004.23

Authors

Macheboeuf, P.,Fisher, D.S.,Brown, T.J.,Zervosen, A.,Luxen, A.,Joris, B.,Dessen, A.,Schofield, C.J. (deposition date: 2006-12-23, release date: 2007-08-14, Last modification date: 2024-10-16)

Primary citation

Macheboeuf, P.,Fisher, D.S.,Brown, T.J.,Zervosen, A.,Luxen, A.,Joris, B.,Dessen, A.,Schofield, C.J.
Structural and Mechanistic Basis of Penicillin-Binding Protein Inhibition by Lactivicins
Nat.Chem.Biol., 3:565-, 2007

PubMed Abstract: 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.

PubMed: 17676039
DOI: 10.1038/NCHEMBIO.2007.21

Experimental method

X-RAY DIFFRACTION (2.4 Å)