Abstract
The emergence of antibiotic-resistant microbial strains has become a public health issue and there is an urgent need to develop new anti-infective molecules. Although natural antimicrobial peptides (AMPs) can exert bactericidal activities, they have not shown clinical efficacy. The limitations of native peptides may be overcome with rational design and synthesis. Here, we provide evidence that the bactericidal activity of a synthetic peptide, GW-Q6, against Pseudomonas aeruginosa is mediated through outer membrane protein OprI. Hyperpolarization/depolarization of membrane potential and increase of membrane permeability were observed after GW-Q6 treatment. Helical structure as well as hydrophobicity was induced by an amphipathic surfactant, sarkosyl, for binding to OprI and possible to membrane. NMR studies demonstrated GW-Q6 is an amphipathic α-helical structure in DPC micelles. The paramagnetic relaxation enhancement (PRE) approach revealed that GW-Q6 orients its α-helix segment (K7-K17) into DPC micelles. Additionally, this α-helix segment is critical for membrane permeabilization and antimicrobial activity. Moreover, residues K3, K7, and K14 could be critical for helical formation and membrane binding while residues Y19 and W20 for directing the C-terminus of the peptide to the surface of micelle. Taken together, our study provides mechanistic insights into the mode of action of the GW-Q6 peptide and suggests its applicability in modifying and developing potent AMPs as therapeutic agents.
Highlights
The progressive increase of antibiotic-resistant bacterial strains has become a severe publichealth problem worldwide [1,2]
GW-Q6 exhibited weaker membranedisrupting ability against POPC with LC100 ! 1.5 μM. These results suggest that GW-Q6 has a strong disrupting activity against negatively charged bacterial membranes but displays much weaker ability against neutrally charged eukaryotic cell membranes [40]
We propose that GW-Q6 may target OprI or fuse with bacterial membrane after being triggered by sarkosyl-like surfactant having an amphiphilic structure with a hydrophobic surface and anionic charge, and exert its antimicrobial activity
Summary
The progressive increase of antibiotic-resistant bacterial strains has become a severe publichealth problem worldwide [1,2]. There is an urgent need to develop new antibiotics with less likelihood to incur evolved resistance. Animals evolutionarily acquire innate abilities from ancestors to identify and resist attacks by microorganisms. GW-Q6 Targets Surface Receptor OprI in Inhibition of Pseudomonas aeruginosa
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