Advances in the Development of Antibiotic Drug Candidates for Urinary Tract Infection Therapy

Urinary tract infections (UTIs) remain one of the most prevalent bacterial infections worldwide, and their complications are increasingly exacerbated by antibiotic resistance. The predominant pathogen, Escherichia coli (E. coli), contributes to both uncomplicated and complicated infections through adhesion and biofilm formation, posing major therapeutic challenges. This review critically examines current and emerging antibiotic drug candidates for UTI therapy, integrating insights from microbiology, clinical studies, and medicinal chemistry. Existing antibiotics for UTI treatment include trimethoprim/sulfamethoxazole, nitrofurantoin, fosfomycin, ciprofloxacin, levofloxacin, cephalexin, ceftriaxone, amoxicillin/clavulanate, doxycycline, and piperacillin/tazobactam. Additionally, Orlynvah and Pivya, two recently approved antibiotics, are discussed for their potential use in UTI therapy. The review also discusses structure-activity relationship (SAR)-guided development of trimethoprim derivatives and heterocyclic analogues targeting dihydrofolate reductase (DHFR), with docking and mechanistic studies proposed for future evaluation. Nonantibiotic strategies, such as mannosides, curli inhibitors, and FimH antagonists, are also being explored as promising anti-adhesion and biofilm-targeting therapies. This review emphasizes the urgent need for novel, resistance-resilient antibacterial agents and highlights recent chemical and biological innovations that could transform future UTI prevention and therapy.