ABSTRACT
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ABSTRACT
The spread of antimicrobial resistance stimulates discovery strategies that place emphasis on mechanisms circumventing the drawbacks of traditional antibiotics and on agents that hit multiple targets. Host defense peptides (HDPs) are promising candidates in this regard. Here we demonstrate that a given HDP sequence intrinsically encodes for tuneable mechanisms of membrane disruption. Using an archetypal HDP (cecropin B) we show that subtle structural alterations convert antimicrobial mechanisms from native carpet-like scenarios to poration and non-porating membrane exfoliation. Such distinct mechanisms, studied using low- and high-resolution spectroscopy, nanoscale imaging and molecular dynamics simulations, all maintain strong antimicrobial effects, albeit with diminished activity against pathogens resistant to HDPs. The strategy offers an effective search paradigm for the sequence probing of discrete antimicrobial mechanisms within a single HDP.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Insect Proteins/chemistry , Insect Proteins/pharmacology , Lipid Bilayers/metabolism , Moths/chemistry , Amino Acid Sequence , Animals , Bacterial Infections/drug therapy , Drug Discovery , Drug Resistance, Bacterial , Humans , Models, Molecular , Phospholipids/metabolismABSTRACT
The spread of bacterial resistance to antibiotics poses the need for antimicrobial discovery. With traditional search paradigms being exhausted, approaches that are altogether different from antibiotics may offer promising and creative solutions. Here, we introduce a de novo peptide topology that-by emulating the virus architecture-assembles into discrete antimicrobial capsids. Using the combination of high-resolution and real-time imaging, we demonstrate that these artificial capsids assemble as 20-nm hollow shells that attack bacterial membranes and upon landing on phospholipid bilayers instantaneously (seconds) convert into rapidly expanding pores causing membrane lysis (minutes). The designed capsids show broad antimicrobial activities, thus executing one primary function-they destroy bacteria on contact.
Subject(s)
Anti-Infective Agents/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Bacteria/drug effects , Capsid/metabolism , Chemistry Techniques, Synthetic/methods , Drug Resistance, Bacterial , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/metabolism , Antimicrobial Cationic Peptides/chemical synthesis , Antimicrobial Cationic Peptides/metabolism , Capsid/ultrastructure , Chromatography, High Pressure Liquid , Cryoelectron Microscopy , Drug Discovery , Humans , Lipid Bilayers/metabolism , Microbial Sensitivity Tests , Microscopy, Electron, Transmission , PhospholipidsABSTRACT
A conceptual design for artificial antimicrobial viruses is described. The design emulates viral assembly and function to create self-assembling peptide capsules that promote efficient gene delivery and silencing in mammalian cells. Unlike viruses, however, the capsules are antimicrobial, which allows them to exhibit a dual biological function: gene transport and antimicrobial activity. Unlike other antimicrobials, the capsules act as pre-concentrated antimicrobial agents that elicit rapid and localised membrane-disrupting responses by converting into individual pores at their precise landing positions on membranes. The concept holds promise for engineering virus-like scaffolds with biologically tuneable properties.
