Antibacterial carbonic anhydrase inhibitors: an update on the recent literature

ABSTRACT

Introduction

The clinically licensed drugs used as antibiotics prevent the microbial growth interfering with the biosynthesis of proteins, nucleic acids, microorganism wall biosynthesis or wall permeability, and microbial metabolic pathways. A serious, emerging problem is the arisen of extensive drug resistance afflicting most countries worldwide.

Areas covered

An exciting approach to fight drug resistance is the identification of essential enzymes encoded by pathogen genomes. Inhibition of such enzymes may impair microbial growth or virulence due to interference with crucial metabolic processes. Genome exploration of pathogenic and nonpathogenic microorganisms has revealed carbonic anhydrases (CAs, EC 4.2.1.1) as possible antibacterial targets.

Expert opinion

Balancing the equilibrium between CO₂ and HCO₃⁻ is essential for microbial metabolism and is regulated by at least four classes of CAs. Classical CA inhibitors (CAIs) such as ethoxzolamide were shown to kill the gastric pathogen Helicobacter pylori in vitro, whereas acetazolamide and some of its more lipophilic derivatives were shown to be effective against vancomycin-resistant Enterococcus spp., with MICs in the range of 0.007–2 µg/mL, better than linezolid, the only clinically used agent available to date. Such results reinforce the rationale of considering existing and newly designed CAIs as antibacterials with an alternative mechanism of action.

KEYWORDS:

• antibacterials
• bacteria
• carbonic anhydrase inhibitor
• sulfonamide
• anion

Article highlights

• Four CA-classes (α, β, γ, and ι) are present in Bacteria.

• Bacteria need CO₂ and HCO₃⁻ for growing.

• CO₂ and HCO₃⁻ are necessary for supporting the central bacterial metabolism.

• Interference with CA activity impairs the growth of the microbe.

• CAs are involved in the survival, pathogenicity, and virulence of several species of human pathogens, such as Helicobacter pylori, Vibrio cholerae, Brucella suis, Salmonella enterica, and Pseudomonas aeruginosa, Enterococcus spp.

• A large number of bacterial CAs have been prepared and characterized as recombinant enzymes.

• Bacterial CAs are inhibited by classical CAIs, such as sulfonamides, sulfamates, sulfamides, (in)organic anions, dithiocarbamates, carboxylic acids and other classes of compounds.

• Ethoxzolamide kills Helicobacter pylori in cell cultures, with low bacterial resistance to this compound being developed

• Acetazolamide and some of its lipophilic derivatives are effective in inhibiting the growth (and killing) vancomycin-resistant Enteroccocci, with efficacy superior to linezolid

• Bacterial CAs represent at this moment promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used agents.

This box summarizes key points contained in the article.

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

This work was in part supported by CNR project NUTR-AGE, FOE- 2019, DSB.AD004.271 (to C Capasso), by the Italian Ministry for University and Research (MIUR), grant PRIN: rot. 2017XYBP2R (to CT Supuran) and by Horizon2020 project Springboard (to CT Supuran).