101 / 101
Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts
96
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
<g class="gr_ gr_40 gr-alert gr_spell
ContextualSpelling ins-del multiReplace" id="40" data-gr-id="40">rrs gene
and
rpsE
gene.
Transition (A1183G), transversion (G1379T), and novel cytosine insertion (926C) mutations
occurred in the <g class="gr_ gr_11 gr-alert gr_spell ContextualSpelling ins-del multiReplace"
id="11" data-gr-id="11">
rrs
gene. Mutant strain susceptibility tests with anti-TB drugs revealed
<g class="gr_ gr_12 gr-alert gr_gramm Grammar only-ins doubleReplace replaceWithoutSep"
id="12" data-gr-id="12">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.