RESISTANCE TO THE NITROHETEROCYCLIC DRUGS

The nitroheterocyclic drugs have been available since the early 1960's for the treatment of anaerobic protozoa. The application of these dru gs has widened since then and they are presently used to treat anaerob ic pathogenic bacteria and protozoa. The activity of the nitroheterocy clic drugs depends on the all-important nitro group attached to the im idazole or furan ring. Although the nitro radicals, generated by reduc tion of the parent drugs, are similar for both families of nitrohetero cyclics, the nitroimidazoles and the nitrofurans, the electron potenti al of each is different and thus the mechanism of action depends on di fferent pathways. The nitroimidazoles depend on reduction by ferredoxi n or flavodoxin. The nitrofurans require nitroreductase activity, but the natural substrate of these enzymes has not been identified. Increa sed use of nitroheterocyclic drugs, in response to drug resistance to other commonly used antibiotics, has in turn resulted in drug resistan ce to a number of nitroheterocyclic drugs. Bacteroides strains and oth er bacteria, including Helicobacter, have developed resistance. Among the protozoa, Trichomonas has developed resistance to metronidazole vi a a number of mechanisms, especially a decrease in drug reduction, as a result of alterations in the electron transport pathways. Resistance to both types of nitroheterocyclic drugs has been reported in Giardia . Although resistance to these drugs is not widespread, their increase d use world-wide as a prophylaxis and in chemotherapy will inevitably result in increased resistance in organisms commonly found in asymptom atic infections, including Trichomonas, Giardia and Entamoeba. However , the variety of substitutions which can be attached to the ring struc tures has led to a great variety of drugs being synthesised, some of w hich are many-fold more active than the commonly prescribed nitroheter ocyclics. With careful administration of currently available drugs and continued interest in synthesising more active compounds, we can opti mistically expect to have useful nitroheterocyclic drugs available for some time.