Structure guided development of potent reversibly binding penicillin binding protein inhibitors

Esther C Y Woon; Astrid Zervosen; Eric Sauvage; Katie J Simmons; Matej Zivec; Steven R Inglis; Colin W G Fishwick; Stanislav Gobec; Paulette Charlier; André Luxen; Christopher J Schofield

doi:10.1021/ml100260x

Structure guided development of potent reversibly binding penicillin binding protein inhibitors

ACS Med Chem Lett. 2011 Jan 11;2(3):219-23. doi: 10.1021/ml100260x. eCollection 2011 Mar 10.

Affiliations

¹ Chemistry Research Laboratory, Department of Chemistry, University of Oxford , 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
² Centre de Recherches du Cyclotron, B30, Universite de Liège , Sart-Tilman, B-4000 Liège, Belgium.
³ Centre d'Ingénierie des Protéines, Université de Liège , Institut de Physique B5, B-4000 Liège, Belgium.
⁴ School of Chemistry, University of Leeds , Leeds LS2 9JT, United Kingdom.
⁵ Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.

Abstract

Following from the evaluation of different types of electrophiles, combined modeling and crystallographic analyses are used to generate potent boronic acid based inhibitors of a penicillin binding protein. The results suggest that a structurally informed approach to penicillin binding protein inhibition will be useful for the development of both improved reversibly binding inhibitors, including boronic acids, and acylating inhibitors, such as β-lactams.

Keywords: Penicillin binding proteins; antibiotic-resistance; antibiotics; boronic acids; transpeptidase-inhibition; β-lactams.