Investigations Into The Mechanisms of Anti-Mycobacterial Drug Resistance Using Antipsychotic Compounds

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.