Mycobacterium tuberculosis β-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs

Abstract

The genome of Mycobacterium tuberculosis (Mtb) encodes three β-carbonic anhydrases (CAs, EC 4.2.1.1) that are crucial for the life cycle of the bacterium. The Mtb β-CAs have been cloned and characterized, and the catalytic activities of the enzymes have been studied. The crystal structures of two of the enzymes have been resolved. In vitro inhibition studies have been conducted using different classes of carbonic anhydrase inhibitors (CAIs). In vivo inhibition studies of pathogenic bacteria containing β-CAs showed that β-CA inhibitors effectively inhibited the growth of pathogenic bacteria. The in vitro and in vivo studies clearly demonstrated that β-CAs of not only mycobacterial species, but also other pathogenic bacteria, can be targeted for developing novel antimycobacterial agents for treating tuberculosis and other microbial infections that are resistant to existing drugs. In this review, we present the molecular and structural data on three β-CAs of Mtb that will give us better insights into the roles of these enzymes in pathogenic bacterial species. We also present data from both in vitro inhibition studies using different classes of chemical compounds and in vivo inhibition studies focusing on M. marinum, a model organism and close relative of Mtb.

In Silico Investigation of Potential Applications of Gamma Carbonic Anhydrases as Catalysts of CO2 Biomineralization Processes: A Visit to the Thermophilic Bacteria Persephonella hydrogeniphila, Persephonella marina, Thermosulfidibacter takaii, and Thermus thermophilus

“…This residue has, however, been observed occasionally coordinating Zn 2+ in EcoCA-γ, resulting in a “closed” conformation. This in turn, resulted in a mechanism similar to the β-CAs in which they switch between “open” and “closed” states [ 42 , 43 ]. This phenomenon was, thus, searched for γ-PhCA and γ-PmCA following MD simulations.…”

Synthesis and Biological Evaluation of Novel Benzhydrylpiperazine-Coupled Nitrobenzenesulfonamide Hybrids

“… 21 An electron-deficient benzene ring with a thiol produces a Meisenheimer complex that dissociates to generate SO 2 , as shown in Figure 3 . 30 Apart from oxidative stress, carbonic anhydrase inhibitors, 31 dihydropteroate synthase and dihydrofolate reductase inhibition, 32 resistance to the aminoglycoside antibiotic kanamycin A, 33 and an undefined mechanism associated with Wag31 33 , 34 may be responsible for desired inhibition.…”

Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii

“…Numerous pieces of evidence support the involvement of CA activity in the survival, pathogenicity and virulence of several species of human pathogens, such as Helicobacter pylori [ 55 , 56 , 57 ], Vibrio cholerae [ 58 ], Brucella suis [ 52 , 59 , 60 , 61 ], Salmonella enterica [ 62 ] and Pseudomonas aeruginosa [ 63 ]. For example, ethoxzolamide ( EZA) was demonstrated to inhibit the V. cholerae virulence in vivo by blocking the cholera toxin gene expression, induced by the bicarbonate produced by the Vibrio CA activity [ 58 ]; this inhibitor can also prejudice the virulence of M. tuberculosis [ 64 ]. Recently, it has been demonstrated that AAZ and some AAZ -based sulfonamides act as potent inhibitors of vancomycin-resistant Enterococcus [ 65 ], which are the leading causes of drug-resistant healthcare-associated infections.…”