Abstract
Antimicrobial peptides (AMPs), which present in the non-specific immune system of organism, are amongst the most promising candidates for the development of novel antimicrobials. The modification of naturally occurring AMPs based on their residue composition and distribution is a simple and effective strategy for optimization of known AMPs. In this study, a series of truncated and residue-substituted derivatives of antimicrobial peptide PMAP-36 were designed and synthesized. The 24-residue truncated peptide, GI24, displayed antimicrobial activity comparable to the mother peptide PMAP-36 with MICs ranging from 1 to 4 µM, which is lower than the MICs of bee venom melittin. Although GI24 displayed high antimicrobial activity, its hemolytic activity was much lower than melittin, suggesting that GI24 have optimal cell selectivity. In addition, the crucial site of GI24 was identified through single site-mutation. An amino acid with high hydrophobicity at position 23 played an important role in guaranteeing the high antimicrobial activity of GI24. Then, lipid vesicles and whole bacteria were employed to investigate the membrane-active mechanisms. Membrane-simulating experiments showed that GI24 interacted strongly with negatively charged phospholipids and weakly with zwitterionic phospholipids, which corresponded well with the data of its biological activities. Membrane permeabilization and flow cytometry provide the evidence that GI24 killed microbial cells by permeabilizing the cell membrane and damaging membrane integrity. GI24 resulted in greater cell morphological changes and visible pores on cell membrane as determined using scanning electron microscopy (SEM) and transmission electron microscope (TEM). Taken together, the peptide GI24 may provide a promising antimicrobial agent for therapeutic applications against the frequently-encountered bacteria.
Highlights
The discovery of antibiotics effectively reduces the happening of infectious diseases and saved countless lives in less than nine decades
Unlike conventional antibiotics that inhibit specific biosynthetic pathways such as cell wall or protein synthesis, the majority of antimicrobial peptides (AMPs) carry out their respective functions via the rapid physical disruption of microbial cell membranes to cause leakage of cell contents leading to cell death [1]
GI24 corresponding to the N-terminal of porcine myeloid antimicrobial peptide-36 (PMAP-36) displayed activity comparable to the full length peptide with minimal inhibitory concentrations (MICs) ranging from 1 to 4 mM, while no antimicrobial activity of PG12 (12-residue C-terminal fragment of PMAP-36) was observed for tested microorganisms
Summary
The discovery of antibiotics effectively reduces the happening of infectious diseases and saved countless lives in less than nine decades. Unlike conventional antibiotics that inhibit specific biosynthetic pathways such as cell wall or protein synthesis, the majority of AMPs carry out their respective functions via the rapid physical disruption of microbial cell membranes to cause leakage of cell contents leading to cell death [1]. This is expected to provide an inherent advantage for AMPs in the clinical setting because it is metabolically ‘costlier’ for most microbial to promote resistance by mutating or repairing its membrane components [8]. There are at least four different commonly used models describing possible AMP membrane-active mechanism that include ‘barrel-stave’, ‘carpet’, ‘toroidal-pore’, and ‘aggregate channel’ models [9,10]
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