Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts

41-POS Board 41 Chlorpromazine Potentiates the Activity of Spectinomycin against Mycobacterium Tuberculosis Vinayak Singh 1 , Elizabeth M. Kigondu 2 , Kelly Chibale 2,1 , Valerie Mizrahi 1 , Digby F. Warner 1 . 1 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 2 Department of Chemistry, University of Cape Town, Cape Town, Western Cape, South Africa. The aim of this study is to explore the mechanism of action of spectinomycin based on a renewed interest to repurpose or reposition the drug for tuberculosis (TB) treatment. Spontaneous spectinomycin resistant Mycobacterium tuberculosis ( Mtb ) mutant strains were generated followed by sequencing of 16S ribosomal RNA rrs gene and rpsE gene. Transition (A1183G), transversion (G1379T), and novel cytosine insertion (926C) mutations occurred in the rrs gene. Mutant strain susceptibility tests with anti-TB drugs revealed absence of cross-resistance. Synergistic interactions initially observed in a combination of spectinomycin and chlorpromazine (CPZ) against Mtb (wild-type) were absent against the mutant strains confirming that spectinomycin was acting “on target.” Moreover, utilizing combination assays, we determined that a synergistic interaction between spectinomycin and CPZ results from CPZ-mediated inhibition of Rv1258c, reinforcing the value of inhibiting efflux as a viable strategy in new TB drug development.

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