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

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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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.

Original languageEnglish
Article numbere1006850
Pages (from-to)1-25
Number of pages25
JournalPLoS Pathogens
Volume14
Issue number2
DOIs
Publication statusPublished - 9 Feb 2018

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Trypanocidal Agents
Neglected Diseases
African Trypanosomiasis
Amine Oxidase (Copper-Containing)
Aldehyde Dehydrogenase
Trypanosoma brucei brucei
Prodrugs
Aldehydes
Amines
Communicable Diseases
Parasites
Therapeutics
benzaldehyde
Metabolic Activation
methylamine

Cite this

Zhang, Ning ; Zoltner, Martin ; Leung, Ka-Fai ; Scullion, Paul ; Hutchinson, Sebastian ; Del Pino, Ricardo C. ; Vincent, Isabel M. ; Zhang, Yong-Kang ; Freund, Yvonne R. ; Alley, Michael R. K. ; Jacobs, Robert T. ; Read, Kevin D. ; Barrett, Michael P. ; Horn, David ; Field, Mark C. / Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. In: PLoS Pathogens. 2018 ; Vol. 14, No. 2. pp. 1-25.
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title = "Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles",
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.",
author = "Ning Zhang and Martin Zoltner and Ka-Fai Leung and Paul Scullion and Sebastian Hutchinson and {Del Pino}, {Ricardo C.} and Vincent, {Isabel M.} and Yong-Kang Zhang and Freund, {Yvonne R.} and Alley, {Michael R. K.} and Jacobs, {Robert T.} and Read, {Kevin D.} and Barrett, {Michael P.} and David Horn and Field, {Mark C.}",
note = "This work was supported by the MRC (www.mrc.ac.uk) (MR/K008749/1 to MCF, DH and MPB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",
year = "2018",
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Zhang, N, Zoltner, M, Leung, K-F, Scullion, P, Hutchinson, S, Del Pino, RC, Vincent, IM, Zhang, Y-K, Freund, YR, Alley, MRK, Jacobs, RT, Read, KD, Barrett, MP, Horn, D & Field, MC 2018, 'Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles', PLoS Pathogens, vol. 14, no. 2, e1006850, pp. 1-25. https://doi.org/10.1371/journal.ppat.1006850

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. / Zhang, Ning; Zoltner, Martin; Leung, Ka-Fai; Scullion, Paul; Hutchinson, Sebastian; Del Pino, Ricardo C.; Vincent, Isabel M.; Zhang, Yong-Kang; Freund, Yvonne R.; Alley, Michael R. K.; Jacobs, Robert T.; Read, Kevin D.; Barrett, Michael P.; Horn, David; Field, Mark C. (Lead / Corresponding author).

In: PLoS Pathogens, Vol. 14, No. 2, e1006850, 09.02.2018, p. 1-25.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

AU - Zhang, Ning

AU - Zoltner, Martin

AU - Leung, Ka-Fai

AU - Scullion, Paul

AU - Hutchinson, Sebastian

AU - Del Pino, Ricardo C.

AU - Vincent, Isabel M.

AU - Zhang, Yong-Kang

AU - Freund, Yvonne R.

AU - Alley, Michael R. K.

AU - Jacobs, Robert T.

AU - Read, Kevin D.

AU - Barrett, Michael P.

AU - Horn, David

AU - Field, Mark C.

N1 - This work was supported by the MRC (www.mrc.ac.uk) (MR/K008749/1 to MCF, DH and MPB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2018/2/9

Y1 - 2018/2/9

N2 - 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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