Elucidating the bactericidal mechanism of action of the linear antimicrobial tetrapeptide BRBR-NH2

Abstract

Linear antimicrobial peptides, with their rapid bactericidal mode of action, are well-suited for development as topical antibacterial drugs. We recently designed a synthetic linear 4-residue peptide, BRBR-NH, with potent bactericidal activity against Staphylococcus aureus (MIC 6.25 μM), the main causative pathogen of human skin infections with an unknown mechanism of action. Herein, we describe a series of experiments conducted to gain further insights into its mechanism of action involving electron microscopy, artificial membrane dye leakage, solution- and solid-state NMR spectroscopy followed by molecular dynamics simulations. Experimental results point towards a SMART (Soft Membranes Adapt and Respond, also Transiently) mechanism of action, suggesting that the peptide can be developed as a topical antibacterial agent for treating drug-resistant Staphylococcus aureus infections.

The Mechanism of Membrane Permeabilization by Peptides: Still an Enigma

“…Interestingly, only a few published leakage curves show the expected behavior for equilibrium pore formation across all peptide concentrations. Instead, what is often observed is a burst of leakage that occurs immediately after peptide is added, followed by a slowing or cessation of leakage that occurs over the subsequent 5-30 minutes (38)(39)(40). In such transient leakage processes, most leakage occurs immediately after addition of peptides to vesicles, or vesicles to peptides.…”

Identification and Rational Design of a Novel Antibacterial Peptide Dermaseptin-AC from the Skin Secretion of the Red-Eyed Tree Frog Agalychnis callidryas

“…Antibiotics have always played an essential role in protecting human health. However, due to the emergence of a large number of resistant bacteria, antibiotics have gradually lost their antibacterial utility [2,3]. Therefore, the development of new antibiotics or other antibacterial substances has become an urgent problem to be solved by the biomedical community [4].…”

A Comprehensive Metabolomics Analysis of Fecal Samples from Advanced Adenoma and Colorectal Cancer Patients

“…In addition of its primordial function as an oxygen carrier, hemoglobin is also a source of endogenous bioactive heme-peptides [37] STVLT and VGAHAGEY, related to antimicrobial peptides (AMPs) that are indispensable components of the innate immune system in various species, including humans, animals and plants, and become the first-line defense against foreign attacks [37][38][39]. AMPs have a broad spectrum of biological activities, including antibacterial, antifungal, antivirus and anticancer [37,[40][41][42]. The presence of STVLT or VGAHAGEY, and especially both, indicates a high probability of being CRC [43]; and the absence of both indicates a high likelihood not to be CRC [43,44].…”