Genomic and Proteomic Studies on the mode of action of Oxaboroles against the African Trypanosome

Jones, Deuan C. and Foth, Bernardo J. and Urbaniak, Michael Daniel and Patterson, Stephen and Ong, Han B. and Berriman, Matthew and Fairlamb, Alan H. (2015) Genomic and Proteomic Studies on the mode of action of Oxaboroles against the African Trypanosome. PLoS Neglected Tropical Diseases, 9 (12). ISSN 1935-2727

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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

Item Type:
Journal Article
Journal or Publication Title:
PLoS Neglected Tropical Diseases
Additional Information:
© 2015 Jones et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/3000
Subjects:
ID Code:
76868
Deposited By:
Deposited On:
03 Dec 2015 09:18
Refereed?:
Yes
Published?:
Published
Last Modified:
27 Oct 2020 05:16