Metronidazole-resistant strains of Trichomonas vaginalis display increased susceptibility to oxygen.
Susceptibility to oxygen and properties relative to oxygen metabolism were compared in metronidazole-resistant and susceptible strains of Trichomonas vaginalis. The study involved clinical isolates displaying the aerobic type of resistance, as well as resistant strains developed in vitro, both with aerobic (MR-3) and anaerobic (MR-5, MR-100) resistance. Elevated sensitivity to oxygen of the resistant clinical isolates was observed. Progressive increase of susceptibility to oxygen also accompanied in vitro development of resistance. No correlation was found between the activity of NADH oxidase and aerobic resistance, while the in vitro derivative with fully developed anaerobic resistance (MR-100) showed about 50% decrease of NADH oxidase activity. The superoxide dismutase (SOD) activity was elevated in both resistant clinical isolates and in in vitro-developed resistant strains. The changes in levels of ferredoxin were insufficient to support ferredoxin deficiency as a cause of aerobic metronidazole resistance. Western blot analysis and electron paramagnetic resonance spectroscopy of purified hydrogenosomes showed that ferredoxin is expressed in aerobically resistant strains and has intact iron-sulfur clusters. Down-regulation of ferredoxin was demonstrated only in the late phase of development of the anaerobic resistance (MR-100). The results support a link between aerobic resistance and defective oxygen scavenging. The increased levels of intracellular oxygen, beneficial to resistant parasites when they interact with the drug, may have adverse effects on their fitness as shown by their increased sensitivity to oxidative stress.
Rasoloson
D
D
Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic.
Tomková
E
E
Cammack
R
R
Kulda
J
J
Tachezy
J
J
D000818:Animals; D000994:Antitrichomonal Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004351:Drug Resistance; D004578:Electron Spin Resonance Spectroscopy; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005288:Ferredoxins / Q000378:metabolism; D006801:Humans; D008795:Metronidazole / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014247:Trichomonas Vaginitis / Q000188:drug therapy / Q000469:parasitology; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
D000994:Antitrichomonal Agents; D005288:Ferredoxins; D009097:Multienzyme Complexes; D008795:Metronidazole; D013482:Superoxide Dismutase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D010100:Oxygen