RESUMEN
Drug-resistant gonorrhea is caused by the bacterial pathogen Neisseria gonorrhoeae, for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits N. gonorrhoeae; however, is not effective at reducing N. gonorrhoeae bioburden in a mouse model. Thus, we sought to optimize the pharmacokinetic properties of the ethoxzolamide scaffold. These efforts resulted in analogs with improved activity against N. gonorrhoeae, increased metabolic stability in mouse liver microsomes, and improved Caco-2 permeability compared to ethoxzolamide. Improvement in these properties resulted in increased plasma exposure in vivo after oral dosing. Top compounds were investigated for in vivo efficacy in a vaginal mouse model of gonococcal genital tract infection, and they significantly decreased the gonococcal burden compared to vehicle and ethoxzolamide controls. Altogether, results from this study provide evidence that ethoxzolamide-based compounds have the potential to be effective oral therapeutics against gonococcal infection.
Asunto(s)
Antibacterianos , Etoxzolamida , Neisseria gonorrhoeae , Neisseria gonorrhoeae/efectos de los fármacos , Animales , Humanos , Ratones , Células CACO-2 , Femenino , Etoxzolamida/farmacología , Etoxzolamida/farmacocinética , Etoxzolamida/síntesis química , Etoxzolamida/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/uso terapéutico , Microsomas Hepáticos/metabolismo , Gonorrea/tratamiento farmacológico , Relación Estructura-Actividad , Pruebas de Sensibilidad Microbiana , Inhibidores de Anhidrasa Carbónica/farmacocinética , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/uso terapéuticoRESUMEN
Neisseria gonorrhoeae is a high-priority pathogen of concern due to the growing prevalence of resistance development against approved antibiotics. Herein, we report the anti-gonococcal activity of ethoxzolamide, the FDA-approved human carbonic anhydrase inhibitor. Ethoxzolamide displayed an MIC50, against a panel of N. gonorrhoeae isolates, of 0.125 µg/mL, 16-fold more potent than acetazolamide, although both molecules exhibited almost similar potency against the gonococcal carbonic anhydrase enzyme (NgCA) in vitro. Acetazolamide displayed an inhibition constant (Ki) versus NgCA of 74 nM, while Ethoxzolamide's Ki was estimated to 94 nM. Therefore, the increased anti-gonococcal potency of ethoxzolamide was attributed to its increased permeability in N. gonorrhoeae as compared to that of acetazolamide. Both drugs demonstrated bacteriostatic activity against N. gonorrhoeae, exhibited post-antibiotic effects up to 10 hours, and resistance was not observed against both. Taken together, these results indicate that acetazolamide and ethoxzolamide warrant further investigation for translation into effective anti-N. gonorrhoeae agents.
Asunto(s)
Acetazolamida/farmacología , Antibacterianos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Etoxzolamida/farmacología , Neisseria gonorrhoeae/efectos de los fármacos , Acetazolamida/síntesis química , Acetazolamida/química , Antibacterianos/síntesis química , Antibacterianos/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Etoxzolamida/síntesis química , Etoxzolamida/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Neisseria gonorrhoeae/enzimología , Relación Estructura-Actividad , Estados Unidos , United States Food and Drug AdministrationRESUMEN
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 × 10-9, 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.
Asunto(s)
Antibacterianos/farmacología , Etoxzolamida/farmacología , Helicobacter pylori/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Etoxzolamida/síntesis química , Etoxzolamida/química , Helicobacter pylori/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide (4, L-643,799) was prepared and the potential utility of each series member as a topically active inhibitor of ocular carbonic anhydrase was determined. In vitro studies showed these esters to be substrates for ocular esterases which liberate 4 during corneal translocation. The most interesting series member, 2-sulfamoyl-6-benzothiazolyl 2,2-dimethylpropionate (22, L-645,151), acting as a prodrug form of 4, was found to enhance delivery through the isolated albino rabbit cornea by 40-fold when compared to the parent phenol 4. Studies in rabbits revealed that 22 is a potent topically active ocular hypotensive carbonic anhydrase inhibitor.
Asunto(s)
Inhibidores de Anhidrasa Carbónica , Etoxzolamida/farmacología , Tiazoles/farmacología , Animales , Benzotiazoles , Inhibidores de Anhidrasa Carbónica/síntesis química , Fenómenos Químicos , Química , Córnea/enzimología , Etoxzolamida/administración & dosificación , Etoxzolamida/síntesis química , Cobayas , Humanos , Presión Intraocular/efectos de los fármacos , Soluciones Oftálmicas , Profármacos/administración & dosificación , Profármacos/síntesis química , Profármacos/farmacología , Conejos , Tiazoles/administración & dosificación , Tiazoles/síntesis químicaRESUMEN
An analogue of ethoxzolamide, 6-hydroxyethoxzolamide, was synthesized to enhance corneal permeability yet retain carbonic anhydrase inhibitory activity for use in lowering intraocular pressure. In a 1% suspension, the analogue caused a small but statistically significant unilateral reduction of IOP when applied to one eye of normal rabbits. When formulated in a gel vehicle, 6-hydroxyethoxzolamide caused a more prolonged and larger reduction in IOP in normal and ocular hypertensive rabbits compared with its effect in suspension or with the parent compound.