Abstract:
The continual emergence of drug resistant strains of Mycobacterium tuberculosis has caused
global public health concerns. This project establishes basis for deciphering diverse resistance
mechanisms in mycobacteria which would lead to the development of novel therapeutic options.
Unique classes of antipsychotic compounds have been found to possess antifungal and anti
mycobacterial activities. The study sought to use antipsychotic compounds and a panel of
phenotype modifying compounds to probe for resistance mechanisms in Mycobacterium
smegmatis. Pairwise drug combinations (480 drug-pair conditions) between antipsychotic
compounds/phenotypic compounds and antimicrobial agents produced resistance breaking
interactions (37%) and resistance inducing interactions (6%) in M. smegmatis. The membrane
disrupting antipsychotic compound, thioridazine, generated resistance breaking effects with a
number of antibiotics with different antimicrobial profiles suggesting cell envelope homeostasis
as a possible mechanism of antimicrobial tolerance and resistance. The DNA damaging agent 4
nitroquinoline oxide produced resistance breaking effects in pairwise combinations with 20
antibiotics tested in the study and disrupted biofilm in M. smegmatis, hence supporting the
evidence that DNA damage repair is a possible mechanism of antibiotic tolerance. Deferoxamine
and sulfometuron which induced biofilm formation in M. smegmatis also promoted
mycobacterial resistance to a number of antibiotics. All antipsychotics tested promoted ethidium
bromide uptake and reduced the rate of extrusion of ethidium bromide in M. smegmatis and
erythromycin-resistant M .smegmatis A. DNA damaging agents inhibited biofilm formation in
M. smegmatis and multidrug resistant erythromycin resistant M. smegmatis A, suggesting DNA
disruption as a biofilm breaking strategy. The study highlights the usefulness of unrelated drugs
and natural products in TB drug discovery while unveiling other determinants of drug resistance.
