Novel carbonic anhydrase inhibitors for the treatment of Helicobacter pylori infection

ABSTRACT

Introduction

Helicobacter pylori, the causative agent of peptic ulcer, gastritis, and gastric cancer encodes two carbonic anhydrases (CA, EC 4.2.1.1) belonging to the α- and β-class (HpCAα/β), which have been validated as antibacterial drug targets. Acetazolamide and ethoxzolamide were also clinically used for the management of peptic ulcer.

Areas covered

Sulfonamides were the most investigated HpCAα/β compounds, with several low nanomolar inhibitors identified, some of which also crystallized as adducts with HpCAα, allowing for the rationalization of the structure–activity relationship. Few data are available for other classes of inhibitors, such as phenols, sulfamides, sulfamates, dithiocarbamates, arylboronic acids, some of which showed effective in vitro inhibition and for phenols, also inhibition of planktonic growth, biofilm formation, and outer membrane vesicles spawning.

Expert opinion

Several recent drug design studies reported selenazoles incorporating seleno/telluro-ethers attached to benzenesulfonamides, hybrids incorporating the EGFR inhibitor erlotinib and benzenesulfonamides, showing K_Is < 100 nM against HpCAα and MICs in the range of 8–16 µg/mL for the most active derivatives. Few drug design studies for non-sulfonamide inhibitors were performed to date, although inhibition of these enzymes may help the fight of multidrug resistance to classical antibiotics which emerged in the last decades also for this bacterium.

KEYWORDS:

• Helicobacter pylori
• carbonic anhydrase
• sulfonamide
• acetazolamide
• famotidine
• hybrids
• carvacrol
• erlotinib

Article highlights

• Helicobacter pylori is the bacterium causing peptic ulcer, gastritis, and gastric cancer.

• Extensive drug resistance and multidrug resistance to clinically used antibiotics has emerged worldwide for many H. pylori strains.

• Two bacterial carbonic anhydrases (CAs) are encoded in the genome of the pathogen, HpCAα and HpCAβ, which started to be considered as attractive drug targets in the last decade.

• Bacterial CAs are emerging as interesting therapeutic targets for many pathogens showing drug resistance to classical antibiotics reverting the resistance in some cases.

• Sulfonamide HpCAα/HpCAβ inhibitors effectively bind these enzymes as shown by X-ray crystallography for the first enzyme and show antibacterial efficacy.

• Phenol inhibitors such as thymol and carvacrol, alone or in combination with clinically used antibiotics, inhibit the planktonic growth of the bacterium, the biofilm formation and the outer membrane vesicles spawning.

• Few drug design studies of non-sulfonamide HpCAα/HpCAβ inhibitors were reported to date.

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

The work from the author’s laboratory was financed by the Italian Ministry for University and Research (MIUR), project FISR2019_04819 BacCAD and EU –Horizon 2020, for the project Springboard [grant agreement No. 951883].