Structure–Activity Relationship for Sulfonamide Inhibition of <i>Helicobacter pylori</i> α-Carbonic Anhydrase

Modak, Joyanta K.; Liu, Yu C.; Supuran, Claudiu T.; Roujeinikova, Anna

doi:10.1021/acs.jmedchem.6b01333

Cited by 57 publications

(33 citation statements)

References 42 publications

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“…Developed as an inhibitor of hCAs, EZA is also known to inhibit activity of H. pylori α-and β-carbonic anhydrases (HpαCA and HpβCA) [12,13]. The crystal structures of HpαCA bound to EZA and related sulfonamides demonstrated that these compounds act as competitive inhibitors mimicking the transition state of the reaction, and that their structure correlates well with their in vitro inhibitory properties [14,15]. These observations suggest that the EZA inhibition of activity of H. pylori carbonic anhydrases likely plays an important role in the mechanism of its antibacterial action, although no spontaneous HpαCA and HpβCA mutants with resistance to EZA have been isolated so far.…”

Section: Open Accessmentioning

confidence: 99%

Antibacterial activity of ethoxzolamide against Helicobacter pylori strains SS1 and 26695

et al. 2020

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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.

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Section: Open Accessmentioning

confidence: 99%

Antibacterial activity of ethoxzolamide against Helicobacter pylori strains SS1 and 26695

et al. 2020

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“…As carbonic anhydrases were considered the likely targets for the anti-H. pylori activity of sulfonamides [12][13][14][15] , the genes for aand b-carbonic anhydrases were sequenced in the parental strain and in MutE. No mutations were found, eliminating the possibility that amino acid changes in these enzymes caused the resistance phenotype.…”

Section: Identification Of Genetic Determinants Linked To Eza Resistancementioning

confidence: 99%

“…Analysis of the crystal structures of HpaCA in complex with either AAZ or MZA 14 revealed that these sulphonamides act as activesite inhibitors that mimic the transition state of the reaction catalysed by the enzyme. Furthermore, the crystal structures of HpaCA in complex with a series of AAZ-related sulphonamides, including EZA, revealed that the mode of sulphonamide binding to HpaCA correlates well with their inhibitory activities 15 . Cumulatively, these data have raised a question of whether the HpaCA inhibition by sulphonamides would result in killing H. pylori.…”

Section: Introductionmentioning

confidence: 98%

Anti-Helicobacter pylori activity of ethoxzolamide

Modak

Tikhomirova

Gorrell

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Ethoxzolamide (EZA), acetazolamide, and methazolamide are clinically used sulphonamide drugs designed to treat non-bacteria-related illnesses (e.g. glaucoma), but they also show antimicrobial activity against the gastric pathogen Helicobacter pylori. EZA showed the highest activity, and was effective against clinical isolates resistant to metronidazole, clarithromycin, and/or amoxicillin, suggesting that EZA kills H. pylori via mechanisms different from that of these antibiotics. The frequency of single-step spontaneous resistance acquisition by H. pylori was less than 5 Â 10 À9 , showing that resistance to EZA does not develop easily. Resistance was associated with mutations in three genes, including the one that encodes undecaprenyl pyrophosphate synthase, a known target of sulphonamides. The data indicate that EZA impacts multiple targets in killing H. pylori. Our findings suggest that developing the approved anti-glaucoma drug EZA into a more effective anti-H. pylori agent may offer a faster and cost-effective route towards new antimicrobials with a novel mechanism of action.

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“…Both metalloenzymes have been described to be essential for acid acclimation, biosynthetic reactions, bacterial survival, and colonization of the stomach and duodenum [67,68,[70][71][72]. They are targeted by sulphonamide antimicrobial agents and phenol-derivatives [68,69,71].…”

Section: Ph Homeostasismentioning

confidence: 99%

Flavodoxins as Novel Therapeutic Targets against Helicobacter pylori and Other Gastric Pathogens

Salillas

Sancho

2020

IJMS

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Flavodoxins are small soluble electron transfer proteins widely present in bacteria and absent in vertebrates. Flavodoxins participate in different metabolic pathways and, in some bacteria, they have been shown to be essential proteins representing promising therapeutic targets to fight bacterial infections. Using purified flavodoxin and chemical libraries, leads can be identified that block flavodoxin function and act as bactericidal molecules, as it has been demonstrated for Helicobacter pylori (Hp), the most prevalent human gastric pathogen. Increasing antimicrobial resistance by this bacterium has led current therapies to lose effectiveness, so alternative treatments are urgently required. Here, we summarize, with a focus on flavodoxin, opportunities for pharmacological intervention offered by the potential protein targets described for this bacterium and provide information on other gastrointestinal pathogens and also on bacteria from the gut microbiota that contain flavodoxin. The process of discovery and development of novel antimicrobials specific for Hp flavodoxin that is being carried out in our group is explained, as it can be extrapolated to the discovery of inhibitors specific for other gastric pathogens. The high specificity for Hp of the antimicrobials developed may be of help to reduce damage to the gut microbiota and to slow down the development of resistant Hp mutants.

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Structure–Activity Relationship for Sulfonamide Inhibition of Helicobacter pylori α-Carbonic Anhydrase

Cited by 57 publications

References 42 publications

Antibacterial activity of ethoxzolamide against Helicobacter pylori strains SS1 and 26695

Antibacterial activity of ethoxzolamide against Helicobacter pylori strains SS1 and 26695

Anti-Helicobacter pylori activity of ethoxzolamide

Flavodoxins as Novel Therapeutic Targets against Helicobacter pylori and Other Gastric Pathogens

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