Novel Pathways and Targets for Combating Antimicrobial Resistance

Introduction: Antimicrobial resistance (AMR) remains a major global health threat driven by β-lactamase-mediated antibiotic hydrolysis, RND-family efflux pump overexpression, horizontal gene transfer, and biofilm-associated phenotypic tolerance. ESKAPE pathogens also combine various resistance mechanisms to survive the majority of antibiotic classes, and poor use of antibiotics maintains selection pressures and promotes the rapid development of multidrug resistance. Methods: We searched peer-reviewed articles in PubMed, Web of Science, Elsevier, and articles indexed in Nature. The ten mechanical categories of therapeutics were assessed, including antivirulence agents, efflux pump inhibitors, biofilm disruptors, quorum-sensing disruptors, CRISPR antimicrobials, bacteriophage therapy, antimicrobial peptides, nanocarrier systems, antibiotic hybrid and potentiator, riboswitch-targeted agents, molecular targets and clinical development status were assessed. Results: FDA-approved agents such as bezlotoxumab and β-lactam/β-lactamase inhibitor combinations, including ceftazidime-avibactam and meropenem-vaborbactam, showed activity against carbapenem-resistant Enterobacterales. CRISPR-engineered bacteriophage LBP-EC01 and chosen antimicrobial peptides are in Phase II/III clinical trials, and riboswitch ligands and antibiotic-peptide hybrids are proving to be preclinically effective with less selection favoring resistance. Discussion: Efflux pump inhibitors are not yet approved due to host transporter cross-reactivity, toxicity, and pharmacokinetic limitations. CRISPR and phage systems have limitations of delivery and uncertainty of regulation, which makes them very unsuccessful during approval. Conclusion: Innovative antimicrobial approaches present groundbreaking options compared to conventional antibiotics by focusing on the mechanisms of pathogenicity instead of merely aiming to eliminate bacteria, which in turn diminishes the selective pressure that leads to the emergence of resistance. The integration of these novel strategies signifies a significant transformation towards sustainable, precision-focused antimicrobial treatment crucial for tackling the worldwide AMR challenge.