Development of carboximidamide small molecule nanogels as potent antimicrobial functional drug delivery systems

The escalating threat of multidrug-resistant (MDR) bacterial infections necessitates innovative antimicrobial strategies with enhanced potency, selectivity, and pharmacokinetic profiles. In this study, chitosan/polyvinyl pyrrolidone (Cs/PVP) nanogels were developed to encapsulate hydrophobic scaffolds (phenyltriazole, phenylthiazole, and phenylguanidine derivatives) to improve solubility, stability, and antimicrobial efficacy. The nanogels exhibited nanoscale dimensions (35-320 nm), uniform spherical morphology, and good colloidal stability. Antimicrobial evaluation revealed significant fold potentiation of activity, with minimal inhibitory concentration (MIC) values reduced up to 64-fold against Gram-positive bacteria, particularly methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and <i>S. epidermidis</i>. DNA gyrase inhibition assays confirmed enhanced enzyme targeting, with TRZS-nanogels achieving an IC₅₀ of 4.44 μg mL^-1, representing a 5.7-fold improvement compared to the free compound. Furthermore, nanogels significantly inhibited biofilm formation, achieving up to 79% inhibition in MRSA and 69% in <i>Pseudomonas aeruginosa</i>. Cytotoxicity studies on human fibroblast cells demonstrated high biocompatibility, with cell viability maintained above 85% at therapeutic concentrations. These findings highlight Cs/PVP nanogels as promising drug delivery systems with dual antibacterial mechanisms, offering improved potency, safety, and potential clinical application against MDR infections.