Structure function and design of polymyxins to enable safer and more potent anti Gram negative agents

Polymyxins, particularly colistin, have re-emerged as last-line antibiotics against multidrug-resistant Gram-negative bacteria. Beyond their clinical revival, they represent a unique platform for medicinal chemistry, owing to their cyclic peptide scaffold, cationic diaminobutyric acid residues, and hydrophobic fatty acyl tail. Recent advances in solid-phase synthesis, structural biology, and molecular pharmacology have revealed critical structure-activity relationships (SAR) that govern antibacterial potency, toxicity, and resistance. This review highlights how chemical modification of Dab side chains, the N-terminal fatty acid, and the cyclic heptapeptide ring has led to next-generation analogues with improved efficacy and safety. We further discuss emerging synthetic strategies, mimetic design, and combination therapies that exploit polymyxin scaffolds to overcome resistance. These insights showcase polymyxins not merely as "old drugs" but as versatile chemical blueprints for innovative lipopeptide therapeutics targeting Gram-negative "superbugs".