Reference : Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Life sciences : Microbiology
Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins
Macheboeuf, Pauline [> > > >]
Fischer, Delphine S [> > > >]
Brown, Tom Jr [> > > >]
Zervosen, Astrid mailto [Université de Liège - ULiège > > Centre de recherches du cyclotron >]
Luxen, André mailto [Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse - Centre de recherches du cyclotron >]
Joris, Bernard mailto [Université de Liège - ULiège > > Centre d'ingénierie des protéines >]
Dessen, Andréa [> > > >]
Schofield, Christopher J. [> > > >]
Nature Chemical Biology
Nature Publishing Group
Yes (verified by ORBi)
New York
[en] penicillin-binding protein ; lactivicin ; penicillin-resistance
[en] 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(1). Lactivicin (LTV; 1) contains separate cycloserine and c-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam(2-4). 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 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.
Centre de Recherches du Cyclotron - CRC ; Centre d'Ingénierie des Protéines - CIP

File(s) associated to this reference

Fulltext file(s):

Restricted access
nchembio.2007.21.pdfPublisher postprint1.73 MBRequest copy

Bookmark and Share SFX Query

All documents in ORBi are protected by a user license.