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New mechanisms of drug resistance in parasitic protozoa
1Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract:
The main line of defense now available against parasitic protozoa--which are responsible for major diseases of humans and domestic animals--is chemotherapy. This defense is being eroded by drug resistance and, with few new drugs in the pipeline, prevention and circumvention of resistance are medical and veterinary priorities. Although studies of resistance mechanisms in parasites have lagged behind similar studies in bacteria and cancer cells, the tools to tackle this problem are rapidly improving. Transformation with exogenous DNA is now possible with all major parasitic protozoa of humans. Hence, putative resistance genes can be tested in sensitive protozoa, allowing an unambiguous reconstruction of resistance mechanisms. Gene cloning, the polymerase chain reaction, and monoclonal antibodies against resistance-related proteins have made it possible to analyze potential resistance mechanisms in the few parasites that can be obtained from infected people. Hence, the prospect of applying new knowledge about resistance mechanisms to parasites in patients is good, even though today virtually all knowledge pertains to parasites selected for resistance in the laboratory. Resistance mechanisms highlighted in this review include: 1. Decrease of drug uptake because of the loss of a transporter required for uptake. This decrease contributes to resistance to arsenicals and diamidines in African trypanosomes. 2. The export of drugs from the parasite by P-glycoproteins and other traffic ATPases. This export could potentially be an important mechanism of resistance, as these proteins are richly represented in the few protozoa analyzed. There are indications that such transmembrane transporters can be involved in resistance to emetine in Entamoeba spp., to mefloquine in Plasmodium spp., and to antimonials in Leishmania spp. 3. The possible involvement of the P-glycoprotein encoded by the Plasmodium falciparum pfmdr1 gene in chloroquine resistance. We present the available data that lead to the conclusion that overproduction of the wild-type version of this protein results in chloroquine hypersensitivity rather than resistance. 4. The involvement of the PgpA P-glycoprotein of Leishmania spp. in low-level resistance to arsenite and antimonials. We raise the possibility that this protein transports glutathione conjugates of arsenite and antimonials rather than the compounds themselves. 5. Loss of drug activation as the main mechanism of metronidazole resistance in Trichomonas and Giardia spp. Recent evidence indicates that a decrease of the proximal cellular electron donor for metronidazole activation, ferredoxin, is the main cause of resistance in Trichomonas. 6. Resistance arising through alteration of drug targets. The amino acid substitutions in the dihydrofolate reductase-thymidylate synthase of Plasmodium spp. are good examples of this mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)
Insights
Drug resistance in parasitic protozoa is a growing threat, necessitating new strategies. Understanding resistance mechanisms, such as decreased drug uptake and altered drug targets, is crucial for developing effective treatments against these diseases.
Area of Science:
- Parasitology
- Molecular Biology
- Drug Discovery
Background:
- Chemotherapy is the primary defense against parasitic protozoa, causing significant human and animal diseases.
- Drug resistance is eroding the effectiveness of current treatments, making prevention and resistance circumvention critical priorities.
- Advancements in molecular tools are improving the study of parasite resistance mechanisms.
Purpose of the Study:
- To review and analyze the known mechanisms of drug resistance in parasitic protozoa.
- To highlight the potential for new knowledge to inform the development of novel therapeutic strategies.
- To discuss the application of modern molecular techniques to study resistance in clinically relevant parasite isolates.
Main Methods:
- Review of existing literature on parasitic protozoan drug resistance mechanisms.
- Analysis of studies utilizing gene cloning, PCR, and monoclonal antibodies.
- Examination of experimental data on parasite transformation and gene function.
Main Results:
- Identified six key drug resistance mechanisms: decreased drug uptake, drug export via ATPases, altered drug targets, loss of drug activation, and potential roles of specific P-glycoproteins.
- Demonstrated that overproduction of Plasmodium falciparum pfmdr1 leads to hypersensitivity, not resistance, to chloroquine.
- Proposed that Leishmania PgpA may transport glutathione conjugates of arsenite and antimonials.
Conclusions:
- Drug resistance in parasitic protozoa is multifaceted, involving transport, metabolism, and target modification.
- Emerging molecular tools enable detailed analysis of resistance mechanisms, even in limited clinical samples.
- Further research into these mechanisms is vital for combating parasitic diseases and overcoming drug resistance.