Department of Pharmacy

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Subject: search.filters.subject.Efflux pump inhibitors (EPIs)

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    Synthesis, biological evaluation and computational studies of acrylohydrazide derivatives as potential Staphylococcus aureus NorA efflux pump inhibitors
    (Elsevier, 2020-11) Kumar, Gautam
    The NorA efflux pump decreases the intracellular concentration of fluoroquinolones (ciprofloxacin, norfloxacin) by effluxing them from Staphylococcus aureus cells. The synthesis of novel acrylohydrazide derivatives was achieved using well-known reactions and were characterized by various spectroscopy techniques. The synthesized 50 compounds were evaluated for the NorA efflux pump inhibition activity against S. aureus SA-1199B (norA++) and K1758 (norA-) strains. The study provided two most active compounds viz. 19 and 52. Compound 19 was found to be most active in potentiating effect of norfloxacin and also it showed enhanced uptake, efflux inhibition in ethidium bromide assay. Further compound 19 also enhanced post antibiotic effect and reduced mutation prevention concentration of norfloxacin. The homology modeling study was performed to elucidate three-dimensional structure of NorA. Docking studies of potent molecules were done to find the binding affinity and interaction with active site residues. Further, all the tested compounds exhibited good ADME and drug-likeness properties in- silico. Based on the in-silico studies and detailed in vitro studies, acrylohydrazides derivatives may be considered as potential NorA EPI candidates.
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    Tackling multidrug-resistant Staphylococcus aureus by natural products and their analogues acting as NorA efflux pump inhibitors
    (Elsevier, 2023-02) Kumar, Gautam
    Staphylococcus aureus (S. aureus) is a pathogen responsible for various community and hospital-acquired infections with life-threatening complications like bacteraemia, endocarditis, meningitis, liver abscess, and spinal cord epidural abscess. Antibiotics have been used to treat microbial infections since the introduction of penicillin in 1940. In recent decades, the abuse and misuse of antibiotics in humans, animals, plants, and fungi, including the treatment of non-microbial diseases, have led to the rapid emergence of multidrug-resistant pathogens with increased virulence. Bacteria have developed several complementary mechanisms to avoid the effects of antibiotics. These mechanisms include chemical transformations and enzymatic inactivation of antibiotics, modification of antibiotics' target site, and reduction of intracellular antibiotics concentration by changes in membrane permeability or by the overexpression of efflux pumps (EPs). The strategy to check antibiotic resistance includes synthesis of the antibiotic analogues, or antibiotics are given in combination with the adjuvant. The inhibitors of multidrug EPs are considered promising alternative therapeutic options with the potential to revive the effects of antibiotics and reduce bacterial virulence. Natural products played a vital role in drug discovery and significantly contributed to the area of infectious diseases. Also, natural products provide lead compounds that sometimes need modification based on structural and biological properties to meet the drug criteria. This review discusses natural products and their derived compounds as NorA efflux pump inhibitors (EPIs).
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    Efflux pump inhibitory potential of indole derivatives as an arsenal against norA over-expressing Staphylococcus aureus
    (ASM, 2023-09) Kumar, Gautam
    NorA, an extensively studied efflux pump in Staphylococcus aureus, has been connected to fluoroquinolone, antiseptic, and disinfection resistance. Several studies have also emphasized how efflux pumps, including NorA, function as the first line of defense of S. aureus against antibiotics. In this study, we have screened some chemically synthesized indole derivatives for their activity as efflux pump inhibitors (EPIs). The derivative SMJ-5 was found to be a potent NorA efflux pump inhibitor among the screened indole derivatives, owing to increased ethidium bromide and norfloxacin accumulation in norA over-expressing S. aureus. The combination of SMJ-5 and ciprofloxacin demonstrated the eradication of S. aureus biofilm and prolonged the post-antibiotic effect more than ciprofloxacin alone. SMJ-5 was able to inhibit staphyloxanthin virulence. In in vitro time-kill trials and in vivo efficacy investigations, the combination enhanced the bactericidal activity of ciprofloxacin against S. aureus. Additionally, reverse transcription PCR results revealed that SMJ-5 also inhibits the NorA efflux pump indirectly at the transcriptional level.