Authors

N Zhang¹; M Zoltner¹; P Scullion¹; D Horn¹; M Field¹;  ¹ Division of Biological Chemistry and Drug Development, School of Life Sciences, University of Dundee

Discussion

The outbreaks of Ebola in Africa and Zika in America reflect a shifting global epidemic landscape of infectious diseases shaped by environmental changes, economic development, regional conflicts and mass migration.  At such a time, though being targeted for eradication by WHO, African trypanomiasis is still devastating local communities as well as remains a threat to the global public health. One of crucial aspects in securing future disease control is to develop new medicines diverged from the ones suffering declined effectiveness in the frontline. Benzoxaboroles are a group of promising candidates in the pipeline. Meanwhile, the rational drug design and prevention of potential resistance in the field requires further insights into both the mode of action (MoA), and the uptake and metabolisms of these compounds. Here, we reveal a contextual oxidative enzymatic cascade responsible for the activation of a series of benzoxaborole derivatives. Through the cascade, the methylamine group in the compounds is first converted by the amine oxidase in the hosts into an aldehyde, which is then transformed by a pathogen-derived aldehyde dehydrogenase, TbALDH3, into a carboxylic acid, rendering the trypanocidal activity. We also provide a molecular insight into how the aldehyde metabolites match the specificity of TbALDH3 as incidental substrates. Overall, this work highlights the importance of understanding the complex and dynamic interaction between the hosts and pathogens, especially in the context of metabolism, in both pharmaceutical development and biological researches.