Antimicrobial peptide class that forms discrete β-barrel stable pores anchored by transmembrane helices
Seth W. Dickey, Dylan J. Burgin, Ama N Antwi, Amer E. Villaruz, Madeline R. Galac, Gordon Y. C. Cheung, Tatiana K. Rostovtseva, L.J. Worrall, Aleksander C. Lazarski, Elio A. Cino, D. Peter Tieleman, Sergey M. Bezrukov, N.C.J. Strynadka, Michaël Otto
Abstract
Bacteriocin peptides are weapons of inter-bacterial warfare and belong to the larger group of antimicrobial peptides (AMPs), which are frequently proposed as alternatives to antibiotics. Many AMPs kill by destroying the target's cytoplasmic membrane using short-lived membrane perturbations. Contrastingly, protein toxins form large pores by stably assembling in the target membrane. Here we describe an AMP class termed TMcins (for transmembrane helix-containing bacteriocin), in which half of the AMP forms a transmembrane helix. This characteristic allows TMcin to assemble into stable and large oligomeric pores. The biosynthetic locus of TMcin, which was broadly active against Gram-positive bacteria, is distributed throughout two major bacterial phyla, yet bears no homology to previously reported bacteriocin biosynthetic gene clusters. Our discovery of an AMP class that achieves pore stability otherwise only found in protein toxins transforms our current understanding of AMP structure and function and underscores the continuing importance of phenotype-initiated investigations in uncovering wholly uncharacterized antimicrobials.