Targeting Bacterial Metalloenzymes: A New Strategy for the Development of Anti-Infective Agents

Jean-Yves      Winum; Stephan      Kohler; Andrea      Scozzafava; Jean-Louis      Montero; Claudiu   T.   Supuran

Abstract

Metalloenzymes are widespread proteins, ubiquitous in all life kingdoms, being involved in various biosynthetic processes. Some of them have been extensively studied in mammals and there are excellent examples for mechanism- based inhibitor design. α-Carbonic anhydrases (CAs), matrix metalloproteinases (MMP), or angiotensin-converting enzyme (ACE), among others, are clinically exploited targets in the treatment or prevention of a variety of diseases such as congestive heart failure, hypertension, glaucoma, epilepsy, and cancer among others. The potential of metalloenzymes as anti-bacterial targets has been taken in consideration only recently. As approximately 3-5% of the bacterial genome encodes metalloenzymes, prokaryotic metalloenzymes such as Peptide Deformylase (PDF), α- β- and γ-CAs and Histidinol Dehydrogenase (HDH), have emerged as new promising antibacterial targets in the search of novel anti-infective agents that lack cross-resistance to existing drugs. Several of these enzymes are required for growth and virulence in several pathogenic species. Their inhibition therefore constitutes an important new approach which has been already successfully applied to the discovery of antibacterial agents active in vivo. This review illustrates and describes the progress which has been made in the design and the discovery of selective inhibitors of bacterial metalloenzymes as new antibacterial agents.

Keywords: Metalloenzymes inhibitors, antibacterial, peptide deformylase, carbonic anhydrase, histidinol dehydrogenase

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