Advancements in Peptidomimetics as a Strategy Against Multidrug Resistance: Fundamentals, Rational Design, Resistance Mechanisms, and Artificial Intelligence

Antimicrobial peptides offer rapid, often membrane centered activity, but their therapeutic translation is limited by proteolytic instability, toxicity, reduced activity under physiological conditions, unfavourable pharmacokinetics, and manufacturing challenges. Peptidomimetics seek to retain the functional logic of antimicrobial peptides while improving these properties. This review presents a unified framework for peptidomimetic based antimicrobial discovery. It describes the fundamentals and classes of antimicrobial peptidomimetics, discusses mechanisms of antibacterial activity and the molecular basis of multidrug resistance. The review also highlights advances in molecular modelling and the growing role of artificial intelligence. A literature search was performed using PubMed, Scopus, Web of Science, and Google Scholar to review experimental, computational, and translational studies on peptidomimetics. Relevant studies were selected. The review examines the fundamentals of peptidomimetics, including key classes, structural modifications, and optimization strategies designed to overcome antimicrobial resistance. The review also highlights that effective antibacterial action involves electrostatic accumulation, selective membrane anchoring, transition into a membrane active conformation, and, in some cases, permeation to intracellular targets. In Gram-negative organisms, lipopolysaccharide organization and Ca²⁺/Mg²⁺ mediated cross linking increases the energetic barrier to membrane engagement. Furthermore, advances in synthetic methodologies, coupled with AI, are expected to enable faster and more efficient synthesis routes. Peptidomimetics seek to redefine antibacterial strategy by encoding resistance resilience into molecular design rather than relying on single target novelty. Their future impact will depend on integrating structure–activity relationships, mechanistic understanding with AI guided design.