SCREENING OF C-9154 ANTIBIOTIC DERIVATIVES FOR INHIBITORY ACTIVITIES ON TRYPANOSOMAL ALTERNATIVE OXIDASE AND THEIR ANTI-TRYPANOSOMAL POTENTIALS
SCREENING OF C-9154 ANTIBIOTIC DERIVATIVES FOR INHIBITORY ACTIVITIES ON TRYPANOSOMAL ALTERNATIVE OXIDASE AND THEIR ANTI-TRYPANOSOMAL POTENTIALS
No Thumbnail Available
Date
2018-07
Authors
IBRAHIM, Bashiru
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
African trypanosomiasis is a neglected tropical disease caused by flagellated parasites of the genus Trypanosoma and Trypanosoma brucei is a representative specie. It is a disease of humans and livestock. Available drugs have unsatisfactory outcomes such as toxicity and emerging resistance hence the need to search for new remedies. The typanosomal alternative oxidase (TAO), a terminal oxidase of the mitochondrial electron transport chain is an essential enzyme for the parasites‟ respiration and aerobic metabolism for ATP. This enzyme is absent in the mammalian host and has been considered an attractive molecular target for drug discovery. In this study, a library of thirty four (34) derivatives of the C-9154 antibiotic was screened for their inhibitory activities on TAO and also for their anti-trypanosomal potentials determined by cessation of motility. Eight of the derivatives were found to significantly reduce the activity of the enzyme with compound 32 eliciting the highest inhibitory potency. Investigation into the inhibition kinetics showed that the compound inhibited the enzyme competitively with Km, Vmaxand Ki values of 393.3 μM, 70.9 μmol/min/mg and 1.25 μM, respectively. Molecular docking studies of the compounds was performed and the predicted binding energies is suggestive of tight binding to the enzyme. Compound 32 had the highest binding affinity -9.0 Kcal/mol, corroborating the inhibitory data. The predictive binding mode of the compound in the enzyme active site suggests strong interactions between the compound and Arg118, Thr219, Leu122, and Leu212. Finally, in vitro test for trypanocidal activity was performed by checking drop or cessation in motility in the presence of the test compounds on Trypanosoma brucei bruceiand Trypanosoma congolense. Interestingly, while ten of the derivatives reduced the motility in both parasites, only compound 32 was trypanocidal in the presence of 5mM glycerol. In conclusion, derivatives of C-9154 antibiotic was found to be trypanocidal through inhibition of TAO.
Description
A THESIS SUBMITTED TO THE SCHOOL OF POSTGRADUATE STUDIES, AHMADU BELLO UNIVERSITY, ZARIA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE AWARD OF MASTER DEGREE IN BIOCHEMISTRY DEPARTMENT OF BIOCHEMISTRY FACULTY OF LIFE SCIENCES AHMADU BELLO UNIVERSITY, ZARIA, NIGERIA
Keywords
SCREENING,, C-9154 ANTIBIOTIC DERIVATIVES,, INHIBITORY ACTIVITIES,, TRYPANOSOMAL ALTERNATIVE OXIDASE,, ANTI-TRYPANOSOMAL,, POTENTIALS,