Emerging Antibacterial Strategies Against Multidrug-Resistant Bacteria: A Systematic Review of Discovery, Clinical Evidence, and Translational Gaps

Abstract

Background: Antimicrobial resistance is projected to directly cause over 39 million deaths between 2025 and 2050, while AMR-associated mortality is expected to increase by nearly three-quarters. Despite this growing crisis, the global antibacterial development pipeline continues to contract, with limited innovation targeting priority multidrug-resistant pathogens. 

Objective: To systematically review recent advances in antibiotic discovery and development, including novel chemical scaffolds, non-traditional antibacterial strategies, and AI-enabled discovery technologies, and to evaluate the quality and translational potential of the available evidence through June 2026. 

Methods: A PRISMA 2020-guided systematic review was conducted using PubMed, MEDLINE, Embase, Scopus, Web of Science, the Cochrane Library, WHO antibacterial pipeline reports, FDA and EMA records, and major clinical trial registries (January 2020 to June 2026). The review was prospectively registered with PROSPERO (CRD420261452452). Eligible studies included novel antibacterial agents, bacteriophages, antimicrobial peptides, antibodies, microbiome-based therapies, and AI-driven discovery platforms with preclinical or clinical evidence. Risk of bias was assessed using validated tools, and findings were synthesized narratively due to substantial heterogeneity. No external funding was received for this review, and no formal certainty of evidence rating was applied, consistent with the narrative, non-pooled nature of the synthesis.

Results: The 2025 WHO pipeline identified 90 clinical-stage and 232 preclinical antibacterial candidates, with only a minority demonstrating novel mechanisms or activity against WHO critical-priority pathogens.Advances included zosurabalpin for carbapenem-resistant Acinetobacter baumannii, AI-discovered antibiotics such as halicin and abaucin, and generative AI-designed antibacterial compounds. Personalized bacteriophage therapy showed promising observational outcomes, whereas gepotidacin became the first new oral antibiotic class approved in decades for uncomplicated urinary tract infection and gonorrhea.

Conclusion: Although significant mechanistic innovation is emerging, the antibacterial pipeline remains inadequate to address the rapidly expanding AMR burden. Greater investment, regulatory support, and well-designed comparative clinical trials are essential to translate these advances into meaningful clinical impact.