An overview of novel antimicrobial carbonic anhydrase inhibitors

ABSTRACT

Introduction

Four different genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) are present in bacteria, α-, β-, γ- and ι-CAs. They play relevant functions related to CO₂, HCO₃⁻/H⁺ ions homeostasis, being involved in metabolic biosynthetic pathways, pH regulation, and represent virulence and survival factors for bacteria in various niches. Bacterial CAs started to be considered druggable targets in the last decade, as their inhibition impairs survival, growth, and virulence of these pathogens.

Areas covered

Significant advances were registered in the last years for designing effective inhibitors of sulfonamide type for Helicobacter pylori α-CA, Neisseria gonorrhoeae α-CA, vacomycin-resistant enterococci (VRE) α- and γ-CAs, for which the in vivo validation has also been achieved. MIC-s in the range of 0.25–4.0 µg/mL for wild type and drug resistant N. gonorrhoeae strains, and of 0.007–2.0 µg/mL for VRE were observed for some 1,3,4-thiadiazole-2-sulfonamides, and acetazolamide was effective in gut decolonization from VRE.

Expert opinion

Targeting bacterial CAs from other pathogens, among which Vibrio cholerae, Mycobacterium tuberculosis, Brucella suis, Salmonella enterica serovar Typhimurium, Legionella pneumophila, Porphyromonas gingivalis, Clostridium perfringens, Streptococcus mutans, Burkholderia pseudomallei, Francisella tularensis, Escherichia coli, Mammaliicoccus (Staphylococcus) sciuri, Pseudomonas aeruginosa, may lead to novel antibacterials devoid of drug resistance problems.

KEYWORDS:

• Carbonic anhydrase
• inhibitors
• sulfonamides
• Helicobacter pylori
• antibiotic drug resistance
• Neisseria gonorrhoeae
• vacomycin-resistant enterococci

Article highlights

• Bacteria encode for at least four distinct CA gene families, α-, β-, γ- and ι-CAs

• Bacterial CAs started to be considered as antimicrobial drug targets in the last decade

• Inhibition of bacterial CAs with sulfonamides, sulfamides, sulfamates, anions, and other classes of inhibitors (phenols, dithiocarbamates, benzoxaboroles, etc.) led to the discovery of many effective in vitro inhibitors.

• Drug design campaigns of sulfonamide inhibitors against Helicobacter pylori α-CA led to effective and bacterial enzyme-selective inhibitors which inhibited the growth of the bacterium without the emergence of drug resistance

• Low nanomolar inhibitors of Neisseria gonorrhoeae α-CA belonging to the 1,3,4-thiadiazole-2-sulfonamide class showed MIC values in the range of 0.25–4.0 µg/mL and had potent anti-gonococcal activity in an animal model of the disease

• Effective inhibitors against vancomycin resistant enterococci (VRE) α- and γ-CAs, belonging to 5-amido-1,3,4-thiadiazole-2-sulfonamides, showed MIC values in the range of 0.007-2.0 µg/mL and led to gut decolonization from VRE more effectively than linezolid, a clinically used drug

• CAs were characterized and their inhibition profile is known in many other pathogenic species, such as Vibrio cholerae, Mycobacterium tuberculosis, Brucella suis, Salmonella enterica serovar Typhimurium, Legionella pneumophila, Porphyromonas gingivalis, Clostridium perfringens, Streptococcus mutans, Burkholderia pseudomallei, Francisella tularensis, Escherichia coli, Mammaliicoccus (Staphylococcus) sciuri, as well as Pseudomonas aeruginosa, but the antibacterial effects were scarcely validated for the moment for many of them.

• Inhibition of bacterial CAs may lead to novel classes of antibacterials with less drug resistance problems compared to presently used such drugs.

Declaration of interest

The authors have no 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Work from the author’s laboratory was financed by the Italian Ministry for University and Research (MIUR), project FISR2019_04819 BacCAD and EU – Horizon2020, for the project Springboard (grant agreement No. 951883).