Redox potential and oxygen concentration as factors in the susceptibility of Helicobacter pylori to nitroheterocyclic drugs.
Metronidazole sensitive (MtzS) and resistant (MtzR) strains of Helicobacter pylori were tested for their sensitivities to eleven nitroheterocyclic drugs of known reduction potential under a wide range of environmental conditions. Under microaerophilic conditions, MtzR strains were sensitive to all the 2-nitroimidazoles, resistant to every 5-nitroimidazole, and slightly sensitive to the nitrothiazole, niridazole. MtzS strains were sensitive to all the nitroimidazoles except for 4(5)-nitroimidazole which has the lowest redox potential of all the drugs investigated. MtzS strains displayed the greatest sensitivity towards niridazole and satranidazole, the latter having the highest redox potential of the 5-nitroimidazoles. High and low oxygen tensions had no effect on the activity of the drugs but periods of anaerobic incubation caused resistant strains to become sensitive to the 5-nitroimidazoles. Superoxide dismutase and catalase were not induced by metronidazole and enzyme levels showed no correlation with resistance patterns. The results show that futile cycling does not occur in H. pylori and that the mechanism of action of the nitroimidazoles is related to their redox potential. Anaerobiosis abolishes resistance to metronidazole which suggests that it may be mediated through the activation of anaerobic metabolic pathways which function less under microaerophilic conditions or not at all.
Smith
M A
MA
Chemotherapy Research Unit, University of East London, UK.
Edwards
D I
DI
D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004352:Drug Resistance, Microbial; D004563:Electrochemistry; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006571:Heterocyclic Compounds; D002374:Catalase; D013482:Superoxide Dismutase; D010100:Oxygen