The microbiome-derived antibacterial lugdunin acts as a cation ionophore in synergy with host peptides

The vast majority of antimicrobial peptides produced by members of the microbiome target the bacterial cell envelope by many different mechanisms. These compounds and their producers have evolved side-by-side with their host and were constantly challenged by the host's immune system. These molecules are optimized to be well tolerated at their physiological site of production, and their modes of action have proven efficient <i>in vivo</i>. Imbalancing the cellular ion homeostasis is a prominent mechanism among antibacterial natural products. For instance, over 120 naturally occurring polyether ionophores are known to date, and antimicrobial peptides with ionophore activity have also been detected in microbiomes. In this study, we elucidated the mechanism underlying the membrane potential-dissipating activity of the thiazolidine-containing cycloheptapeptide lugdunin, the first member of the fibupeptides discovered in a commensal bacterium from the human nose, which is a promising future probiotic candidate that is not prone to resistance development.