High efflux pump activity and gene expression at baseline linked to poor tuberculosis treatment outcomes

Abstract

Phenotypic TB drug resistance, also known as drug tolerance, has been previously attributed to slowed bacterial growth in vivo. The increased activity and expression of efflux systems can lower the intracellular concentration of many antibiotics thus reducing their efficacy. We hypothesized that efflux pump activation andexpression could be a risk factor for TB drug tolerance in patients initiated on treatment. Analyses of geneexpression levels of six select efflux pumps associated with drug tolerance in Mycobacterium tuberculosis and itscorrelation with the cells ability to efflux ethidium bromide (a common efflux substrate) were assayed. Efflux pump gene expression differed significantly between the strains from treatment failures and treatmentsuccesses. Efflux of ethidium bromide by M. tuberculosis isolates revealed that isolates from treatment failuresrapidly efflux ethidium bromide more than isolates from treatment successes or the H37Rv control strains.The efflux pumps efpA, jefA (Rv2459c), Rv1258c, p55 and mmpL7 may have a role in TB drug tolerance.Quantifying the expression levels of M. tuberculosis efflux pump genes may be a new method to diagnoseclinically persistent tuberculosis. High efflux pump activity and expression at baseline can be associated withtuberculosis treatment failure even when the Mycobacterium tuberculosis does not have established resistancemutations.Journal of Medical and Biomedical Sciences (2017) 6(1), 8-17Keywords: drug resistance, Efflux, Mycobacterium tuberculosis, expression, treatment outcome