Structure-Guided Design of Cell Wall Biosynthesis Inhibitors That Overcome beta-Lactam Resistance in Staphylococcus aureus (MRSA).

Contreras-Martel, Carlos; Amoroso, Ana Maria; Woon, Esther C.Y.; Zervosen, Astrid; Inglis, Steven; Martins, Alexandre; Verlaine, Olivier; Rydzik, Anna M.; Job, Viviane; Luxen, André; Joris, Bernard; Schofield, Christopher J.; Dessen, Andréa

doi:10.1021/cb2001846

Article (Scientific journals)

Structure-Guided Design of Cell Wall Biosynthesis Inhibitors That Overcome beta-Lactam Resistance in Staphylococcus aureus (MRSA).

Contreras-Martel, Carlos; Amoroso, Ana Maria; Woon, Esther C.Y. et al.

2011 • In ACS Chemical Biology

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/100343

DOI
10.1021/cb2001846

PubMed
21732689

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Keywords :

penicillin-binding proteins; boronic acid; MRSA

Abstract :

[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.

Research Center/Unit :

GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
CIP - Centre d'Ingénierie des Protéines - ULiège

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Contreras-Martel, Carlos

Amoroso, Ana Maria ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Woon, Esther C.Y.

Zervosen, Astrid

Inglis, Steven

Martins, Alexandre; Université de Liège - ULiège > Centre d'ingénierie des protéines

Verlaine, Olivier

Rydzik, Anna M.

Job, Viviane; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse

Luxen, André ; Université de Liège - ULiège > Département des sciences de la vie > Physiologie et génétique bactériennes

More authors (3 more)

Language :

English

Title :

Structure-Guided Design of Cell Wall Biosynthesis Inhibitors That Overcome beta-Lactam Resistance in Staphylococcus aureus (MRSA).

Publication date :

2011

Journal title :

ACS Chemical Biology

ISSN :

1554-8937

eISSN :

1554-8929

Publisher :

American Chemical Society, Washington, United States - Washington

Peer reviewed :

Peer Reviewed verified by ORBi

Name of the research project :

Eur-Intafar

Funders :

UE - Union Européenne
Belgian Program on Interuniversity Poles of Attraction

Available on ORBi :

since 18 October 2011

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