PLOS Pathogens
PLOS Pathogens
5 years ago

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

Yong-Kang Zhang, Michael P. Barrett, Michael R. K. Alley, Yvonne R. Freund, Mark C. Field, Robert T. Jacobs, Martin Zoltner, David Horn, Ricardo C. del Pino, Sebastian Hutchinson, Ka-Fai Leung, Kevin D. Read, Isabel M. Vincent, Paul Scullion, Ning Zhang
Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.

Publisher URL: http://journals.plos.org/plospathogens/article

DOI: 10.1371/journal.ppat.1006850

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