Evaluating quinone based compounds for their antitrypanosomatid properties
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Human African trypanosomiasis (HAT) is caused by the protozoan parasite
Trypanosoma brucei. The use of existing drug regimens is controversial as they are
toxic, have limited efficacy with resistance on the rise. Therefore, there is an urgent
need for new therapies. One group of compounds that are being exploited or
evaluated in treating infectious diseases and cancer are the quinones, with these
agents mediating their cytotoxic activities by acting as prodrugs or inhibiting key
metabolic pathways. Here, we report the screening of a quinone-based compound
library against bloodstream form T. brucei and against the related parasites
Trypanosoma cruzi and Leishmania major, the causative agents of Chagas disease
and cutaneous leishmaniasis, respectively. This analysis demonstrated that the most
potent compounds were those that possessed an aziridinyl 1,4-benzoquinone (ABQs)
core with the most effective displaying a 50% growth inhibitory concentrations of <
1 μM against all three pathogens. Using RH1, the archetypal ABQ, as a selective
agent, a combination of a T. brucei whole genome loss of function assay and drug
selection studies demonstrated that these compounds function as prodrugs with the
activation mechanism catalysed by a type I nitroreductase (NTR). Functional studies
using T. brucei that express altered levels of NTR further demonstrated the
importance of this enzyme in activating the majority of quinone-based moieties
tested. Using genetic approaches, we next demonstrated that following NTRmediated
activation the resultant products go on to promote formation of interstrand
crosslinks (ICLs) within the parasites’ genomes: T. brucei lacking the DNA repair
enzyme SNM1, a nuclease that specifically fixes ICL damage, were more susceptible
to ABQs than controls. In conclusion, ABQs are potent antiparasitic prodrugs
although mammalian toxicity studies indicate these compounds may not be suitable
potential therapies for systemic infections although they are of interest as genetic
tools for probing gene function.
Authors
Meredith, Emma LouiseCollections
- Theses [3704]