Drug targets and mechanisms of resistance in the anaerobic protozoa

The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entam oeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E . histolytica can form abscesses and invade other organs, where it can be f atal if left untreated. T. vaginalis infection is a sexually transmitted in fection causing vaginitis and acute inflammatory disease of the genital muc osa. T. vaginalis has also been reported in the urinary tract fallopian tub es, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respi ratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mor tality as well as predisposing to human immunodeficiency virus infection, A IDS, and cervical cancer. All three organisms lack mitochondria and are sus ceptible to the nitroimidazole metronidazole because of similar low-redox-p otential anaerobic metabolic pathways. Resistance to metronidazole and othe r drugs has been observed clinically and in the laboratory. Laboratory stud ies have identified the enzyme that activates metronidazole, pyruvate:ferre doxin oxidoreductase, to its nitroso form and distinct mechanisms of decrea sing drug susceptibility that are induced in each organism. Although the ni troimidazoles have been the drug family of choice for treating the anaerobi c protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been dem onstrated for each agent and the mechanism of resistance has been investiga ted. Metronidazole resistance in T. vaginalis is well documented, and the p rincipal mechanisms have been defined Bypass metabolism, such as alternativ e oxidoreductases, have been discovered in both organisms. Aerobic versus a naerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazo le resistance in E. histolytica have recently been investigated ruing labor atory-induced resistant isolates. Instead of downregulation of the pyruvate :ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, inclu ding superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resist ant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa i s discussed as well as the value of studies of the epidemiology of resistan ce.