title: Bortezomib inhibits bacterial and fungal β-carbonic anhydrases.
abstract: Inhibition of the β-carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic fungi (Cryptococcus neoformans, Candida albicans, Candida glabrata, Malassezia globosa) and bacteria (three isoforms from Mycobacterium tuberculosis, Rv3273, Rv1284 and Rv3588), as well from the insect Drosophila melanogaster (DmeCA) and the plant Flaveria bidentis (FbiCA1) with the boronic acid peptidomimetic proteosome inhibitor bortezomib was investigated. Bortezomib was a micromolar inhibitor of all these enzymes, with KIs ranging between 1.12 and 11.30μM. Based on recent crystallographic data it is hypothesized that the B(OH)2 moiety of the inhibitor is directly coordinated to the zinc ion from the enzyme active site. The class of boronic acids, an under-investigated type of CA inhibitors, may lead to the development of anti-infectives with a novel mechanism of action, based on the pathogenic organisms CA inhibition.
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000201:enzymology*; D000069286:Bortezomib / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004331:Drosophila melanogaster; D005658:Fungi / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D002257:Carbonic Anhydrase Inhibitors; D000069286:Bortezomib; D002256:Carbonic Anhydrases
keywords: Boronic acid; Bortezomib; Carbonic anhydrase; Drosophila melanogaster; Pathogenic bacteria; Pathogenic fungi