Reference : Structure-Guided Design of Cell Wall Biosynthesis Inhibitors That Overcome beta-Lacta...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Structure-Guided Design of Cell Wall Biosynthesis Inhibitors That Overcome beta-Lactam Resistance in Staphylococcus aureus (MRSA).
Contreras-Martel, Carlos [> > > >]
Amoroso, Ana Maria mailto [Université de Liège - ULiège > > Centre d'ingénierie des protéines]
Woon, Esther C.Y. [> > > >]
Zervosen, Astrid mailto [> > > >]
Inglis, Steven [> > > >]
Martins, Alexandre [Université de Liège - ULiège > > Centre d'ingénierie des protéines]
Verlaine, Olivier mailto [> > > >]
Rydzik, Anna M. [> > > >]
Job, Viviane [Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse]
Luxen, André mailto [Université de Liège - ULiège > Département des sciences de la vie > Physiologie et génétique bactériennes]
Joris, Bernard mailto [> > > >]
Schofield, Christopher J. [> > > >]
Dessen, Andréa [ > > ]
ACS Chemical Biology
American Chemical Society
Yes (verified by ORBi)
[en] penicillin-binding proteins ; boronic acid ; MRSA
[en] beta-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering beta-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to 11 different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low beta-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP inhibitors for circumventing beta-lactam resistance and opens avenues for the development of novel antibiotics that target Gram-positive pathogens.
Centre de Recherches du Cyclotron - CRC ; Centre d'Ingénierie des Protéines - CIP
Union Européenne = European Union - UE = EU ; Belgian Program on Interuniversity Poles of Attraction

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