Bacterial, fungal and protozoan carbonic anhydrases as drug targets

Abstract

Introduction: The carbonic anhydrases (CAs, EC 4.2.1.1), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, as well as in the growth and virulence of pathogens belonging to bacteria, fungi and protozoa.

Areas covered: CAs belonging to at least four genetic families, the α-, β-, γ- and η-CAs, were discovered and characterized in many pathogens: i) Bacteria encode enzymes from one or more such families, which were investigated as potential drug targets. Inhibition of bacterial CAs by sulfonamides/phenol derivatives lead to inhibition of growth of the pathogen for Helicobacter pylori, Mycobacterium tuberculosis, Brucella suis; ii) Fungi encode for α- and β-CAs, and inhibitors of the sulfonamide, thiol or dithiocarbamate type inhibited the growth of some of them (Malassezia globosa, Candida albicans, Crytpococcus neoformans, etc) in vivo; and iii) Protozoa encode α-, β- or η-CAs. Sulfonamide, thiols and hydroxamates effectively killed such parasites (Trypanosoma cruzi, Leishmania donovani chagasi, Plasmodium falciparum) in vivo.

Expert opinion: None of the microorganism CAs is validated as drug targets as yet, but the inhibitors designed against many such enzymes showed interesting in vitro/in vivo results. By interfering with the activity of CAs from microorganisms, both pH homeostasis as well as crucial biosynthetic reactions are impaired, which lead to significant antiinfective effects, not yet exploited for obtaining pharmacological agents. As resistance to the clinically used antiinfectives is a serious healthcare problem worldwide, inhibition of parasite CAs may constitute an alternative approach for obtaining such agents with novel mechanisms of action.

Keywords:

• antiinfective
• bacteria
• carbonic anhydrases
• fungi
• hydroxamate
• inhibitors
• pathogens
• protozoa
• sulfonamide
• thiols
• X-ray

Declaration of interest

Research from the authors’ laboratories was financed by several EU projects (Euroxy, DeznIT, Metoxia, Gums and Joints and Dynano). C Capasso has received sponsorship from PNRA and CT Supuran has received sponsorship from FP7 Grant Metoxia Dynano. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

This box summarizes key points contained in the article.