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MetaboLights MTBLS452 - GNPS 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.

INSTRUMENT(S): Thermo Scientific instrument model|1000494

ORGANISM(S): Trypanosoma Brucei|5691

SUBMITTER: Ning Zhang

PROVIDER: MSV000085875 | GNPS | Sat Aug 01 12:11:00 BST 2020

REPOSITORIES: GNPS

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Project description:Biogenic amine-producing bacteria are responsible for the production of basic nitrogenous compounds, such as histamine, cadaverine, tyramine and putrescine, after foods spoil due to microorganisms. In the present work, we applied a shotgun proteomics approach to quickly and easily characterize 15 different foodborne strains of biogenic amine-producing bacteria. A total of 10673 peptide spectrum matches (PSMs) belonging to 4081 nonredundant peptides and corresponding to 1811 annotated proteins were identified. With the results, relevant functional pathways were determined and the strains were differentiated into different Euclidean hierarchical clusters. Moreover, a predicted protein‒protein interaction network of biogenic amine foodborne strains was created. The whole confidence network contains 260 nodes and 1973 interactions. Most of the identified proteins were related to pathways and networks of energy, putrescine metabolism and host‒virus interaction. In addition, a total of 556 nonredundant peptides were identified as virulence factors, and most of these peptides corresponded to functions such as toxins, antimicrobial compound production, antimicrobial resistance, additional resistances and tolerances, host colonization and immune evasion, ABC transporters, phage proteins, and alternative virulence factors and proteins involved in horizontal transfer. Potential species-specific peptide biomarkers were screened. Thus, 77 species-specific peptide biomarkers belonging to 64 different proteins were proposed to identify 10 species (Enterobacter aerogenes, Enterobacter cloacae, Hafnia alvei, Klebsiella oxytoca, Morganella morganii, Proteus mirabilis, Proteus penneri, Proteus vulgaris, Raoutella planticola, Stenotrophomonas maltophilia). All of these results constitute the first major dataset of peptides and proteins of seafood biogenic amine-producing strains. This repository may be useful for further studies, for the development of new therapeutic treatments for food intoxication and for tracking microbial sources in foodstuffs.

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MetaboLights MTBLS452 - GNPS Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles.

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