{
    "abstract": "Recently, World Health Organization declared antimicrobial resistance as the third greatest threat to human health. Absence of known cross-resistance, new class, new target, and a new mode of action are few major strategies being undertaken by researches to combat multidrug resistant pathogen. PPEF.3HCl, a bisbenzimidazole was developed as highly potent antibacterial agent against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens, targeting topoisomerase IA. The present work encompasses a radical on-site generation of In-situ nanosuspension of PPEF.3HCl with enhanced efficacy against methicillin resistant S. aureus in septicemia model. We have generated instantaneously a PPEF.3HCl nanosuspension (IsPPEF.3HCl-NS) by mixing optimized monophasic PPEF.3HCl preconcentrate in propylene glycol into an aqueous medium comprising tween 80 as stabilizer. The IsPPEF.3HCl-NS showed precipitation efficiency of\u00a0>\u00a090\u00a0%, average particle size\u00a0<\u00a0500\u00a0nm, retained upto 5\u00a0h, a negative zeta potential and bi/trimodal particle size distribution. Differential scanning calorimetry, X-ray diffraction confirmed partial amorphization and transmission electron microscopy revealed spherical particles. IsPPEF.3HCl-NS was non-hemolytic and exhibited good stability in serum. More significantly, it exhibited a\u00a0\u223c\u00a01.6-fold increase in macrophage uptake compared to free PPEF.3HCl in the RAW 264.7 macrophage cell line. Confocal microscopy revealed accumulation of IsPPEF.3HCl-NS within the lysosomal compartment and cell cytosol, proposing high efficacy. In terms of antimicrobial efficacy, IsPPEF.3HCl-NS outperforms free PPEF.3HCl against clinical methicillin sensitive and resistant S. aureus strains. In a pivotal experiment, IsPPEF.3HCl-NS exhibited over 83\u00a0% survival at 8\u00a0mg/kg.bw and an impressive reduction of\u00a0\u223c\u00a04-5 log-fold in bacterial load, primarily in the kidney, liver and spleen of septicemia mice. IsPPEF.3HCl-NS prepared by the In-situ approach, coupled with enhanced intramacrophage delivery and superior efficacy, positions IsPPEF.3HCl-NS as a pioneering and highly promising formulation in the battle against antimicrobial resistance.",
    "authors": [
        {
            "affiliation": "Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai 400019, Maharashtra, India.",
            "firstname": "Amit S",
            "initials": "AS",
            "lastname": "Lokhande"
        },
        {
            "affiliation": "Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.",
            "firstname": "Vikas",
            "initials": "V",
            "lastname": "Maurya"
        },
        {
            "affiliation": "Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.",
            "firstname": "Komal",
            "initials": "K",
            "lastname": "Rani"
        },
        {
            "affiliation": "Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.",
            "firstname": "Palak",
            "initials": "P",
            "lastname": "Parashar"
        },
        {
            "affiliation": "Vardhaman Medical College Hospital, Safdarjung Hospital, New Delhi 110029, India.",
            "firstname": "Rajni",
            "initials": "R",
            "lastname": "Gaind"
        },
        {
            "affiliation": "Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India; CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal 700032, India. Electronic address: vtandon@iicb.res.in.",
            "firstname": "Vibha",
            "initials": "V",
            "lastname": "Tandon"
        },
        {
            "affiliation": "Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai 400019, Maharashtra, India. Electronic address: pvdevarajan@gmail.com.",
            "firstname": "Padma V",
            "initials": "PV",
            "lastname": "Devarajan"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2024 Elsevier B.V. All rights reserved.",
    "doi": "10.1016/j.ijpharm.2024.123982",
    "journal": "International journal of pharmaceutics",
    "keywords": [
        "Antimicrobial resistance",
        "In-situ nanosuspension",
        "Macrophage delivery",
        "PPEF.3HCl",
        "Sepsis"
    ],
    "methods": null,
    "publication_date": "2024-03-10",
    "pubmed_id": "38460770",
    "results": null,
    "title": "Polydispersity-mediated high efficacy of an in-situ aqueous nanosuspension of PPEF.3HCl in methicillin resistant Staphylococcus aureus sepsis model.",
    "xml": "<Element 'PubmedArticle' at 0x7885032e9df0>"
}