ArticlePLoS pathogens2018
Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles.
Article in PLoS pathogens, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Traditional Medicinal Ranunculaceae Species from Romania and Their In Vitro Antioxidant, Antiproliferative, and Antiparasitic Potential.International journal of molecular sciences · 2024Article
- Phenotypic screening reveals a highly selective phthalimide-based compound with antileishmanial activity.PLoS neglected tropical diseases · 2024Article
- The critical role of mode of action studies in kinetoplastid drug discovery.Frontiers in drug discovery · 2023Article
- The 4-Aminomethylphenoxy-Benzoxaborole AN3057 as a Potential Treatment Option for Primary Amoebic Meningoencephalitis.Antimicrobial agents and chemotherapy · 2023Article
- The role of invariant surface glycoprotein 75 in xenobiotic acquisition by African trypanosomes.Microbial cell (Graz, Austria) · 2023Article
- Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole.PLoS neglected tropical diseases · 2021Article
- Establishment of quantitative RNAi-based forward genetics in Entamoeba histolytica and identification of genes required for growth.PLoS pathogens · 2021Article
- Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series.Microorganisms · 2021Article
- Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.PLoS pathogens · 2020Article
- Article
- Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites.Microorganisms · 2020Review
- Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes.The Journal of biological chemistry · 2020Article
- New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story.Tropical medicine and infectious disease · 2020Review
- Article
- Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics.The Journal of biological chemistry · 2019Review
- Clinical and veterinary trypanocidal benzoxaboroles target CPSF3.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing.PLoS pathogens · 2018Article
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Authors and funding
15 authors.
Funding
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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