Research Article: Genomic and Proteomic Studies on the Mode of Action of Oxaboroles against the African Trypanosome

Date Published: December 18, 2015

Publisher: Public Library of Science

Author(s): Deuan C. Jones, Bernardo J. Foth, Michael D. Urbaniak, Stephen Patterson, Han B. Ong, Matthew Berriman, Alan H. Fairlamb, Michael P. Pollastri.

Abstract: SCYX-7158, an oxaborole, is currently in Phase I clinical trials for the treatment of human African trypanosomiasis. Here we investigate possible modes of action against Trypanosoma brucei using orthogonal chemo-proteomic and genomic approaches. SILAC-based proteomic studies using an oxaborole analogue immobilised onto a resin was used either in competition with a soluble oxaborole or an immobilised inactive control to identify thirteen proteins common to both strategies. Cell-cycle analysis of cells incubated with sub-lethal concentrations of an oxaborole identified a subtle but significant accumulation of G2 and >G2 cells. Given the possibility of compromised DNA fidelity, we investigated long-term exposure of T. brucei to oxaboroles by generating resistant cell lines in vitro. Resistance proved more difficult to generate than for drugs currently used in the field, and in one of our three cell lines was unstable. Whole-genome sequencing of the resistant cell lines revealed single nucleotide polymorphisms in 66 genes and several large-scale genomic aberrations. The absence of a simple consistent mechanism among resistant cell lines and the diverse list of binding partners from the proteomic studies suggest a degree of polypharmacology that should reduce the risk of resistance to this compound class emerging in the field. The combined genetic and chemical biology approaches have provided lists of candidates to be investigated for more detailed information on the mode of action of this promising new drug class.

Partial Text: Human African trypanosomiasis (HAT) is caused by two subspecies of the unicellular parasite Trypanosoma brucei, an infection which is transmitted by the bite of a tsetse fly. HAT progresses through a haemo-lymphatic stage into a meningo-encephalitic stage [1] and has a fatality rate close to 100% if left untreated [2]. The disease is also a key factor in maintaining the poverty cycle, and patients are often discriminated against or abandoned [3]. The reporting of new cases of HAT has fallen to below 7,000 in 2011 [4]. However, the disease has previously resurged from even lower levels in the 1980s and 1990s [5]. Current estimates place 70 million people at risk with more than 5 million living in areas of high or very high risk for contracting HAT [4].



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