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

Abstract

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 Staphylococcus aureus (MRSA) and S. epidermidis. 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 Pseudomonas aeruginosa. 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.