Diamidine; Genomics; Drug resistance; Suramin; Molecular mechanism; Aquaporin; Arsenical; Trypanosoma brucei; Pentamidine; Melarsoprol; Human African trypanosomiasis; Sleeping sickness
Kalel Vishal C, Mäser Pascal, Sattler Michael, Erdmann Ralf, Popowicz Grzegorz M (2018), Come, sweet death: targeting glycosomal protein import for antitrypanosomal drug development, in Current Opinion in Microbiology
, 46, 116-122.
Wiedemar Natalie, Graf Fabrice E., Zwyer Michaela, Ndomba Emiliana, Kunz Renggli Christina, Cal Monica, Schmidt Remo S., Wenzler Tanja, Mäser Pascal (2018), Beyond immune escape: a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei Suramin resistance in T . brucei, in Molecular Microbiology
, 107(1), 57-67.
Jeacock Laura, Baker Nicola, Wiedemar Natalie, Mäser Pascal, Horn David (2017), Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity, in PLOS Pathogens
, 13(3), e1006307-e1006307.
Graf Fabrice E., Ludin Philipp, Arquint Christian, Schmidt Remo S., Schaub Nadia, Kunz Renggli Christina, Munday Jane C., Krezdorn Jessica, Baker Nicola, Horn David, Balmer Oliver, Caccone Adalgisa, de Koning Harry P., Mäser Pascal (2016), Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense, in Cellular and Molecular Life Sciences
, 73(17), 3387-3400.
Human African trypanosomiasis (HAT, also known as sleeping sickness) is caused by the haemoflagellate parasites Trypanosoma brucei rhodesiense and T. b. gambiense, and transmitted by the tsetse fly. It is a fatal disease, there is no vaccine, and the available drugs are not satisfactory due to their adverse effects and lack of oral bioavailability. Nevertheless, the prevalence is reclining and HAT may actually be one of the few parasitoses that can be eliminated. This, however, will require new and better drugs. Until then, the current drugs pentamidine, suramin, melarsoprol, and eflornithine/nifurtimox need to be used in a sustainable way, which requires an understanding of the molecular mechanisms of drug resistance. In our current SNF grant we have been investigating the well-known phenomenon of melarsoprol/pentamidine cross-resistance (MPXR) by comparative genomics of susceptible and resistant T. b. rhodesiense lines. We have identified a new point mutation in the adenosine transporter gene TbAT1 that may be involved in drug resistance, and we have demonstrated that the aquaglyceroporin TbAQP2 is missing in the MPXR T. b. rhodesiense. Clinical T. b. gambiense isolates with an MPXR phenotype had a mutant version of the aquaglyceroporin, a chimera between the two tandem genes TbAQP2 and TbAQP3. The MPXR T. b. rhodesiense carried a further mutation, arginine131 to leucin in the RNA-binding protein TbUBP1. Finally, we have generated three stable, isogenic T. b. rhodesiense lines that are resistant to suramin and cross-resistant to trypan blue. Here we propose to continue and possibly finish these lines of research. We shall determine the individual and combined effects on MPXR of the mutations detected in the lab, investigate the function of the newly identified TbAQP2 / TbAQP3 chimera, and test whether the observed MPXR phenotype in the field can be reverted by expression of wild-type TbAQP2. The mutations underlying suramin resistance will be studied by transcriptome sequencing. The anticipated results will be directly applicable to the field and at the same time provide fundamental insights into the biology and pharmacology of trypanosomes.