Department of Pharmacy

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Subject: search.filters.subject.Drug resistance

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    Natural products and their analogues acting against Mycobacterium tuberculosis: A recent update
    (Wiley, 2023-04) Kumar, Gautam
    Tuberculosis (TB) remains one of the deadliest infectious diseases caused by Mycobacterium tuberculosis (M.tb). It is responsible for significant causes of mortality and morbidity worldwide. M.tb possesses robust defense mechanisms against most antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. Thus, the efficacy of existing front-line drugs is diminishing, and new and recurring cases of TB arising from multidrug-resistant M.tb are increasing. TB begs the scientific community to explore novel therapeutic avenues. A precise knowledge of the compounds with their mode of action could aid in developing new anti-TB agents that can kill latent and actively multiplying M.tb. This can help in the shortening of the anti-TB regimen and can improve the outcome of treatment strategies. Natural products have contributed several antibiotics for TB treatment. The sources of anti-TB drugs/inhibitors discussed in this work are target-based identification/cell-based and phenotypic screening from natural products. Some of the recently identified natural products derived leads have reached clinical stages of TB drug development, which include rifapentine, CPZEN-45, spectinamide-1599 and 1810. We believe these anti-TB agents could emerge as superior therapeutic compounds to treat TB over known Food and Drug Administration drugs.
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    Tackling nontuberculous mycobacteria by repurposable drugs and potential leads from natural products
    (Bentham Science, 2024-06) Kumar, Gautam
    Nontuberculous Mycobacteria (NTM) refer to bacteria other than all Mycobacterium species that do not cause tuberculosis or leprosy, excluding the species of the Mycobacterium tuberculosis complex, M. leprae and M. lepromatosis. NTM are ubiquitous and present in soils and natural waters. NTM can survive in a wide range of environmental conditions. The direct inoculum of the NTM from water or other materials is most likely a source of infections. NTMs are responsible for several illnesses, including pulmonary alveolar proteinosis, cystic fibrosis, bronchiectasis, chronic obstructive pneumoconiosis, and pulmonary disease. Recent reports suggest that NTM species have become insensitive to sterilizing agents, antiseptics, and disinfectants. The efficacy of existing anti-NTM regimens is diminishing and has been compromised due to drug resistance. New and recurring cases of multidrug-resistant NTM strains are increasing. Thus, there is an urgent need for ant-NTM regimens with novel modes of action. This review sheds light on the mode of antimicrobial resistance in the NTM species. Then, we discussed the repurposable drugs (antibiotics) that have shown new indications (activity against NTM strains) that could be developed for treating NTM infections. Also, we have summarised recently identified natural leads acting against NTM, which have the potential for treating NTM-associated infections
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    Advances in the synthesis of diarylpyrimidine as potent non-nucleoside reverse transcriptase inhibitors: biological activities, molecular docking studies and structure-activity relationship: a critical review
    (Bentham Science, 2023-04) Murugesan, Sankaranarayanan
    Acquired immunodeficiency syndrome (AIDS) is an ailment that is caused primarily by the Human immunodeficiency virus (HIV), which is the main agent responsible for this deadly disease. Of all the different inhibitors employed to curtail the menace caused by this deadly virus, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been cutting edge in the fight against AIDS. Over the past few years, the diaryl pyrimidine family and its derivatives have shown promising NNRTI properties attributed to their characteristic flexibility, targeting of conserved residues of reverse transcriptase, positional adaptability and, importantly, the formation of hydrogen bonds, which altogether led to the generation of secondgeneration NNRTIs. This breakthrough in the DAPY derivatives led to the development of TMC278 (rilpivirine) and TMC125 (etravirine), the two most recently approved NNRTIs by the FDA because of their low cytotoxicity, superior activities against mutant strains and WT HIV-1, excellent potency and high specificity. However, new challenges loom on the DAPY derivatives: the disappointing pharmacokinetic properties and accelerated emergence of resistance (particularly, K1013N and Y181C mutations, which are the two most important HIV-1 mutations that persist in most of the FDA-approved regimens), which implores further research to develop novel HIV-1 NNRTIs. In this review, we detail the reported different synthetic pathways for diaryl pyrimidine modification from published articles from 2010 to 2022, their biological activities, in addition to molecular docking studies and structure-activity relationships to uncover the possible molecular contributions that improved or reduced the NNRTIs properties. In a nutshell, the research findings provide valuable insights into the various modifications of the DAPY derivatives to develop novel NNRTIs.
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    Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle
    (Elsevier, 2023-04) Roy, Aniruddha
    Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disulfiram (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenvironment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.8, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.