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

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

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Authors

  • Ning Zhang
  • Martin Zoltner
  • Ka-Fai Leung
  • Paul Scullion
  • Sebastian Hutchinson
  • Ricardo C. Del Pino
  • Isabel M. Vincent
  • Yong-Kang Zhang
  • Yvonne R. Freund
  • Michael R. K. Alley
  • Robert T. Jacobs
  • Kevin D. Read
  • Michael P. Barrett
  • David Horn
  • Mark C. Field (Lead / Corresponding author)

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Original languageEnglish
Article numbere1006850
Number of pages25
JournalPLoS Pathogens
Volume14
Issue number2
DOIs
StatePublished - 9 Feb 2018

Abstract

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.

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    © 2018 Zhang 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.

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