Antibacterial activity of ethoxzolamide against Helicobacter pylori strains SS1 and 26695

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.

Anion Inhibition Studies of the Beta-Carbonic Anhydrase from Escherichia coli

“…The comparison with the β-CA from V. cholerae (K I = 451 nM) showed that the E. coli enzyme with a K I of 227 nM is two times more susceptible to AZA inhibition. These results are of extreme importance in the field of the inhibition of bacterial CAs because they prove that, even if these enzyme catalyze the same reaction, they can show a different inhibition pattern, whose investigation can lead to the discovery of novel inhibitors, which may impair the microbial growth as well as their virulence [57].…”

Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori

“…Today, we know that a high percentage of people infected with H. pylori have superficial chronic gastritis. Besides, if left untreated, both H. pylori infection and inflammation can persist for decades, and sometimes even for all the lifetime ( Rahman et al, 2020 ). Over the years, it has learnt that H. pylori causes a chronic inflammatory process, the peptic ulcer in the stomach and duodenum, the portion of the small intestine that originates from the pylorus ( Zhu et al, 2020 ).…”

“…Other than acetazolamide, ethoxzolamide ( EZA ) can be considered a potential drug for developing new anti- H. pylori inhibitors since it kills the bacterium in cell cultures ( Modak et al, 2019 ). Besides, EZA resistance did not develop easily in the H. pylori strains (P12, SS1,m and 26695) used for the experiments, and the compound seems to target multiple pathways since resistance acquisition was due to mutations associated with other genes than CAs ( Rahman et al, 2020 ). In this context, we stress the fact that, recently, it has been demonstrated that the well documented vancomycin-resistant enterococci (VRE) might be addressed by targeting the Enterococcus CAs using a modified scaffold of acetazolamide (an inhibitor of the carbonic anhydrases) ( Kaur et al, 2020 ).…”

GraphMS: Drug Target Prediction Using Graph Representation Learning with Substructures

“…After consulting relevant medical literature, it was found that EZA has potential to treat duodenal ulcer and will be developed into a new anti-Helicobacter drug [31]. Chronic inflammation is closely related to various human diseases, such as cancer, neurodegenerative diseases, and metabolic diseases [32]. Among these, abnormal DNA methylation occurs to some extent, and the enzymatic activity of DNMTs increases.…”