Abstract
With the rise of bacterial resistance to conventional antibiotics, re-purposing of Food and Drug Administration (FDA) approved drugs currently used to treat non-bacteria related diseases as new leads for antibacterial drug discovery has become an attractive alternative. Ethoxzolamide (EZA), an FDA-approved diuretic acting as a human carbonic anhydrase inhibitor, is known to kill the gastric pathogenic bacterium Helicobacter pylori in vitro via an, as yet, unknown mechanism. To date, EZA activity and resistance have been investigated for only one H. pylori strain, P12. We have now performed a susceptibility and resistance study with H. pylori strains SS1 and 26695. Mutants resistant to EZA were isolated, characterized and their genomes sequenced. Resistance-conferring mutations were confirmed by backcrossing the mutations into the parent strain. As with P12, resistance to EZA in strains SS1 and 26695 does not develop easily, since the rate of spontaneous resistance acquisition was less than 10−8. Acquisition of resistance was associated with mutations in 3 genes in strain SS1, and in 6 different genes in strain 26695, indicating that EZA targets multiple systems. All resistant isolates had mutations affecting cell wall synthesis and control of gene expression. EZA’s potential for treating duodenal ulcers has already been demonstrated. Our findings suggest that EZA may be developed into a novel anti-H. pylori drug.
Highlights
Helicobacter pylori is a significant human pathogen causing gastric and duodenal ulcers which, if left untreated, can lead to cancers such as mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma [1, 2]
Ethoxzolamide (EZA)—known under the name Cardrase—is an Food and Drug Administration (FDA)-approved antiglaucoma drug that acts by inhibiting the human metalloenzyme carbonic anhydrase which catalyzes the interconversion of C O2 and bicarbonate [7, 8]
Antimicrobial activity of EZA against H. pylori strains SS1 and 26695 is time‐ and concentration‐dependent It has been previously shown that EZA displays antimicrobial activity against H. pylori strains SS1 (MIC = 0.2 mM, minimum bactericidal concentrations (MBCs) = 0.4 mM) and 26695 (MIC = 0.3 mM, MBC = 0.5 mM) [11]
Summary
Helicobacter pylori is a significant human pathogen causing gastric and duodenal ulcers which, if left untreated, can lead to cancers such as mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma [1, 2]. With the rise of antibiotic resistance, the efficacy of existing treatment regimes has gradually decreased over the years [3,4,5], and the World Health Organization (WHO) recognized the urgent need for novel anti-H. pylori therapies in 2017 by listing clarithromycin-resistant H. pylori among other high priority pathogens for antimicrobial research development [6]. Owing to the spread of bacterial resistance to conventional antibiotics, re-purposing of Food and Drug Administration (FDA) approved drugs currently used to treat non-bacteria related diseases as new leads for antibacterial drug discovery has been recognized as an attractive alternative. EZA has come to attention in the H. pylori field of research due to its unexpected ‘side effect’ of healing stomach ulcers. The additional fact that 2 years following treatment, the ulcer recurrence rate in the tested subjects (11% [9]) was significantly lower than that typically observed with classical antacid drugs (34– 79%), and close to that achieved by the antibiotic-based
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
