Authors
N Zhang1; N Zhang2; M Zoltner1; M Zoltner2; P Scullion1; P Scullion2; K Leung3; S Hutchinson1; S Hutchinson2; R Canavate del Pino1; R Canavate del Pino2; M Barret4; K Read1; K Read2; D Horn1; D Horn2; M Field1; M Field2;
1 Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee; 2 Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee; 3 Department of Pathology, University of Cambridge; 4 Institute of Infection, Immunity and Inflammation, University of Glasgow
Discussion
The rapid spread of antimicrobial resistance is a global urgency in public health. To take on this tremendous challenge, it requires collective efforts towards understanding the mode of actions (MoAs) of antimicrobial medicines both in current use and under development. As part of these efforts, we looked into the MoAs of benzoxaboroles, a group of emerging novel antimicrobials, in Trypanosoma brucei first with a genomic RNAi library screening. The result led us to unravel the potential biological functions involved in determining the efficacy of the benzoxaboroles in the parasites. Especially, we discovered a mechanism underlying the activation of the aminomethylphenoxy derivatives. It is dependent on an enzymatic cascade that consists of an amine oxidase (AO) from the host and an aldehyde dehydrogenase (ALDH) from the parasite. Both enzymatic activities are indispensable for metabolizing the aminomethyphenoxy benzoxaboroles as pro-drugs first into the aldehyde metabolites, and further into the carboxyl acid products as the active form. Overall, our work reveals a novel drug metabolic pathway through the hosts and the pathogens, and addresses the potential risk of resistance development in future application in treating trypanosomiasis with one group of benzoxaborole derivatives.
