• Indian J Med Res · Feb 2023

    Dodecanoic acid & palmitic acid disarms rifampicin resistance by putatively targeting mycobacterial efflux pump Rv1218c.

    • Christy Rosaline Nirmal, Sam Ebenezer Rajadas, Mahizhaveni Balasubramanian, Divya Magdaline, Naresh Babu Chilamakuru, Rajkumar Dinesh, A Radhakrishnan, Ramalingam Paraman, Rajesh Mondal, and Azger DusthackeerV NVNDepartment of Bacteriology, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India..
    • Department of Bacteriology, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu; Achira Labs Pvt. Ltd., Bengaluru, Karnataka, India.
    • Indian J Med Res. 2023 Feb 1; 157 (2&3): 192203192-203.

    Background & ObjectivesDrug-resistant tuberculosis (TB) jeopardizes the treatment process with poor outcomes. Efflux pumps (EPs) belonging to the ABC transporter family in Mycobacterium tuberculosis confer resistance to rifampicin (RMP) besides genetic mutations thus serving as a target for a potential adjunct therapeutic inhibitory molecule. Rv1218c is one such pump that was previously reported to be active in multidrug-resistant TB clinical isolates.MethodsIn this study, the inhibition potential of Rv1218c-EP was tested on 8 molecules that were shortlisted by in silico methods. These molecules were subjected to the minimum inhibitory concentration (MIC) determination, checkerboard drug combination assay, ethidium bromide-DNA binding assay, and in vitro and ex vivo cytotoxicity assay.ResultsBased on the outcome of the study, two molecules dodecanoic acid (DA) and palmitic acid (PA) were found to be potential enough to decrease the MIC of RMP by 8 to 1000 folds against multidrug-resistant clinical isolates and Rv1218c expressing recombinant Mycobacterium smegmatis.Interpretation & ConclusionsThese molecules were also found to reduce the time taken by RMP to kill these drug-resistant Mycobacteria to 48 h, unlike control isolates that survived more than 240 h of RMP exposure. The functional concentration of both molecules was non-toxic to the epithelial and blood mononuclear cells. With further comprehensive scientific validation, PA and DA could be recommended as adjunct therapeutic molecules with first-line anti-TB drugs to treat drug-resistant TB.

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