Literature review: Antibiotic resistance in the diabetic microenvironment: A comprehensive review of biochemical and cellular mechanisms

Infections in patients with diabetes mellitus (DM) present a severe clinical challenge, often characterized by high rates of treatment failure and an increased risk of lower-limb amputations. Traditional management relies on systemic antibiotics, which frequently prove ineffective due to antimicrobial resistance (AMR) and the protective barrier of bacterial biofilms. This review comprehensively examines how the diabetic tissue microenvironment—characterized by chronic hyperglycemia, tissue ischemia, advanced glycation end-products (AGEs) accumulation, and local hypoxia—synergistically drives biochemical and cellular mechanisms of resistance. Hyperglycemia suppresses innate immune functions, blunting neutrophil chemotaxis and causing excessive, pathological Neutrophil Extracellular Trap (NET) formation, which stabilizes rather than eliminates bacterial biofilms. Concurrently, macrophage polarization is arrested in a pro-inflammatory M1-like state, driving chronic non-resolving inflammation and matrix metalloproteinase-9 (MMP-9) upregulation. At the host-pathogen interface, pathogens exploit interstitial glucotoxicity to amplify quorum sensing (QS) networks, precipitating phenotypic tolerance via metabolic dormancy (persister cells). To bypass these barriers, next-generation responsive biomaterials, advanced delivery systems, and non-chemical physical approaches (such as super-oxidized solutions and DACC-impregnated dressings) are emerging as promising immune-aware adjunctive therapies. Integrating precise molecular diagnostics with strict metabolic regulation and biofilm-disrupting modalities is essential to transform diabetic wound care from reactive to proactive, ensuring effective infection control and functional tissue regeneration.