Resistance mechanisms and emerging therapies for Proteus mirabilis

Antimicrobial resistance (AMR) in Proteus mirabilis represents a critical challenge for both clinical medicine and food safety. This opportunistic Gram-negative pathogen transmits through contaminated food chains and exhibits intrinsic, acquired, and adaptive resistance mechanisms. Intrinsic resistance is driven by constitutive lipopolysaccharide modifications, efflux pumps, and chromosomal β-lactamases. Meanwhile, horizontal gene transfer mediates the acquisition of extended-spectrum β-lactamases, AmpC enzymes, carbapenemases, and aminoglycoside-modifying enzymes. Adaptive traits, including swarming motility, urease-driven alkalinization, and crystalline biofilm formation, further enhance tolerance and persistence. Conventional antibiotics are increasingly ineffective against multidrug resistant (MDR) and extensively drug resistant (XDR) strains, highlighting an urgent need for innovative therapeutic approaches. Complementary strategies such as phage therapy, CRISPR-Cas gene editing, nanoparticles, urease and swarming inhibitors, and plant-derived phytochemicals, have emerged as promising alternatives. Each approach offers unique advantages such as biofilm disruption, precision targeting, or multi-site antimicrobial activity, but faces limitations related to delivery, toxicity, or potency. Future directions require standardized manufacturing, rapid diagnostics, and innovative trial designs that integrate combination therapies to maximize efficacy while minimizing resistance risks. By advancing multi-targeted interventions, the scientific and clinical communities can counteract the resilience of P. mirabilis and safeguard public health and food systems.