Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These host-defense peptides compromise the integrity of microbial cell membranes and thus evade pathways by which bacteria develop rapid antibiotic resistance. Although more than 1,700 host-defense peptides have been identified, the structural and mechanistic basis of their action remains speculative. This impedes the desired rational development of these agents into next-generation antibiotics. We present the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and MD simulations of human dermcidin in membranes that reveal the antibiotic mechanism of this major human antimicrobial, found to suppress Staphylococcus aureus growth on the epidermal surface. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidate the unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes. Our study unravels the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at atomistic level. The results may form a foundation for the structure-based design of peptide antibiotics.
by Chen Songa, Conrad Weichbrodt, Evgeniy S. Salnikov, Marek Dynowski, Björn O. Forsberg, Burkhard Bechinger, Claudia Steinem, Bert L. de Groot, Ulrich Zachariae and Kornelius Zeth
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Antimicrobial peptides (AMPs) provide an important first-line defense against bacteria and fungi in multicellular organisms. They do so by targeting the microbial cell membrane, but their precise mechanisms of action are not well understood. Song et al. used a combination of x-ray crystallography, electrophysiology, and molecular dynamics simulations to better understand the mechanism of one such AMP: dermcidin (DCD). DCD is secreted into human sweat and found on the skin. It is active against a range of bacteria, including methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis. The authors' analysis revealed that DCD forms a hexameric barrel-like channel of elongated α helices in bacterial membranes. Stabilization of the channel required the presence of zinc. The channel formed was highly permeable to water and ions and so was a major membrane disruptor. This ability to disrupt the transmembrane potential of bacterial cell membranes can lead to rapid cell death and thus provide protective antimicrobial activity to the host.
by Kristen L. Mueller
Via Freddy Monteiro