The team hopes the findings will lead to the development of new tests for current and new drugs to treat Human African Trypanosomiasis (HAT).
HAT is usually fatal if left untreated. The T. brucei parasite is transmitted by the tsetse fly and ultimately attacks the central nervous system. Due to the absence of a vaccine for sleeping sickness, chemotherapy is of major importance. During the early stages of the disease, pentamidine is typically the only drug available. Diagnosis is often late however, and, in these cases, the arsenic-based drug melarsoprol is often used, despite the fact that the therapy itself kills around 5% of patients. This desperate situation is made worse by the current and increasing incidence of melarsoprol resistance in up to 30% of patients in some areas. Cross resistance among the melarsoprol-pentamidine drug classes was reported over 60 years ago but understanding of the underlying mechanism remains incomplete.
The findings, published in Proceedings of the National Academy of Sciences. USA, are based on the analysis of a pair of water and glycerol channels, known as aquaglyceroporins. In a study earlier this year, some of the same scientists identified two genes that are involved in the action of both pentamidine and melarsoprol. Both genes encode channels that can transport water and glycerol. The new research – which was a collaboration between LSHTM and the University of Glasgow and funded by the Wellcome Trust and the Medical Research Council – revealed that trypanosomes lacking just one of the genes, the AQP2 gene, were resistant to both drugs and that this gene alone could explain the previously observed drug resistance. They also found that the same gene was specifically disrupted in a drug-resistant strain generated in the laboratory several years previously.
Taken together, the results suggest that the AQP2 channel allows both drugs to enter the cell. If AQP2 disruption also explains clinical cases of resistance, a test based on the AQP2 gene could improve prospects for tackling resistance when it arises.
Lead researcher Dr David Horn, Reader in Molecular Biology at LSHTM, said: “Disrupting AQP2 is probably akin to turning off a tap, reducing the flow of drugs into the cell. One important question now is whether disruption of the AQP2 gene can explain cases of drug resistance in patients. If so then we can look to develop a test based on this gene that could help to tackle drug resistance in the field when it arises.”
Baker N et al. Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes. Proc. Natl. Acad. Sci. USA. 2012 (in press).
London School of Hygiene & Tropical Medicine