Abstract: The increasing threat of bacterial infections has created an urgent need for novel antibiotics. Herein, we report a novel polymyxin analog, PL-082, modified at its N-terminal lipid and first amino acid. Distinct from conventional polymyxins, which are exclusively active against Gram-negative bacteria, PL-082 exhibits expanded antibacterial activity against both Gram-positive and Gram-negative bacteria. Through NMR and molecular dynamics simulations, we reveal that the strong interactions between PL-082 and POPG phospholipids—a dominant component of Gram-positive bacterial membrane—account for its unique activity against Gram-positive bacteria. Beyond elucidating the antibacterial mechanism of the novel antibiotic PL-082, this work also provides promising avenues for the development of potent, broad-spectrum antibiotics.

Key words: Polymyxin analog, Gram-positive bacteria, POPG phospholipids