02545nas a2200277   4500008004100000022001400041245012300055210006900178260000800247300001100255490000800266520161900274653001301893653002601906653001401932653001601946653001901962653001701981653003101998100002102029700002702050700002202077700002402099700001802123856012602141       2021                        eng d  a0882-401000aPNA-mediated efflux inhibition as a therapeutic strategy towards overcoming drug resistance in Mycobacterium smegmatis0 aPNAmediated efflux inhibition as a therapeutic strategy towards   cFEB  a1047370 v1513 a<p>The emergence of antibiotic-resistant strains of Mycobacterium tuberculosis and the decelerating development of new and effective antibiotics has impaired the treatment of tuberculosis (TB). Efflux pump inhibitors (EPIs) have the potential to improve the efficacy of existing anti-TB drugs although with toxicity limitations. Peptide nucleic acids (PNAs), oligonucleotide mimics, by virtue of their high nucleic acid binding specificity have the capability to overcome this drawback. We, therefore, investigated the efflux pump inhibitory properties of a PNA designed against an efflux pump of Mycobacterium smegmatis. LfrA, an efflux pump found in M. smegmatis, is majorly involved in conferring innate drug resistance to this strain and, therefore, was selected as a target for gene silencing via PNA. qRT-PCR and EtBr assays confirmed the EPI activity of the anti-lfrA PNA. On testing the effect of the anti-lfrA PNA on the bactericidal activity of a fluoroquinolone, norfloxacin, we observed that 5 mu M of anti-lfrA PNA in combination with norfloxacin led to an enhanced killing of up to 2.5 log-fold against wild-type and a lab-generated multidrug resistant strain, exemplifying its potential in countering resistance. Improved efficacy was also observed against intra-macrophage mycobacteria, where the drug-PNA combination enhanced bacterial clearance by 1.3 log-fold. Further, no toxicity was observed with PNA concentrations up to 4 times higher than the efficacious anti-lfrA PNA concentration. Thus, PNA, as an adjuvant, presents a novel and viable approach to rejuvenate anti-TB therapeutics.</p>
10aAdjuvant10aAntibiotic resistance10aAntisense10aEfflux pump10aGene silencing10aMycobacteria10aPeptide nucleic acid (PNA)1 aGhosh, Saptarshi1 aCotta, Karishma, Berta1 aHande, Aniket, A.1 aFernandes, Moneesha1 aMehra, Sarika  uhttps://library.ncl.res.in/content/pna-mediated-efflux-inhibition-therapeutic-strategy-towards-overcoming-drug-resistance