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Bacterial carbonic anhydrases as drug targets: toward novel antibiotics?

ABSTRACT: Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the ?-, ?-, and/or ?-CA families. In the last decade, the ?-CAs from Neisseria spp. and Helicobacter pylori as well as the ?-class enzymes from Escherichia coli, H. pylori,Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, and Haemophilus influenzae have been cloned and characterized in detail. For some of these enzymes the X-ray crystal structures were determined, and in vitro and in vivo inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates reported. Although efficient inhibitors have been reported for many such enzymes, only for Neisseria spp., H. pylori, B. suis, and S. pneumoniae enzymes it has been possible to evidence inhibition of bacterial growth in vivo. Thus, bacterial CAs represent promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets.

SUBMITTER: Supuran CT

PROVIDER: S-EPMC3132667 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Bacterial carbonic anhydrases as drug targets: toward novel antibiotics?

Supuran Claudiu T CT

Frontiers in pharmacology 20110705

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, the α-CAs from Neisseria spp. and Helicobacter pylori as well as the β-class enzymes from Escherichia coli, H. pylori,Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, and Haemophilus influenzae have been cloned and ...[more]

PMID: 21779249

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Project description:BACKGROUND: The genomes of many insect and parasite species contain beta carbonic anhydrase (?-CA) protein coding sequences. The lack of ?-CA proteins in mammals makes them interesting target proteins for inhibition in treatment of some infectious diseases and pests. Many insects and parasites represent important pests for agriculture and cause enormous economic damage worldwide. Meanwhile, pollution of the environment by old pesticides, emergence of strains resistant to them, and their off-target effects are major challenges for agriculture and society. METHODS: In this study, we analyzed a multiple sequence alignment of 31 ?-CAs from insects, some parasites, and selected plant species relevant to agriculture and livestock husbandry. Using bioinformatics tools a phylogenetic tree was generated and the subcellular localizations and antigenic sites of each protein were predicted. Structural models for ?-CAs of Ancylostoma caninum, Ascaris suum, Trichinella spiralis, and Entamoeba histolytica, were built using Pisum sativum and Mycobacterium tuberculosis ?-CAs as templates. RESULTS: Six ?-CAs of insects and parasites and six ?-CAs of plants are predicted to be mitochondrial and chloroplastic, respectively, and thus may be involved in important metabolic functions. All 31 sequences showed the presence of the highly conserved ?-CA active site sequence motifs, CXDXR and HXXC (C: cysteine, D: aspartic acid, R: arginine, H: histidine, X: any residue). We discovered that these two motifs are more antigenic than others. Homology models suggested that these motifs are mostly buried and thus not well accessible for recognition by antibodies. CONCLUSIONS: The predicted mitochondrial localization of several ?-CAs and hidden antigenic epitopes within the protein molecule, suggest that they may not be considered major targets for vaccines. Instead, they are promising candidate enzymes for small-molecule inhibitors which can easily penetrate the cell membrane. Based on current knowledge, we conclude that ?-CAs are potential targets for development of small molecule pesticides or anti-parasitic agents with minimal side effects on vertebrates.

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Bacterial carbonic anhydrases as drug targets: toward novel antibiotics?

Publications

Bacterial carbonic anhydrases as drug targets: toward novel antibiotics?

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