Antimicrobial Peptides

Abstract

Antimicrobial peptides (AMPs), important effector molecules of the innate immune system, also provide templates for designing novel antibiotics. Protegrin, an especially potent AMP found in porcine leukocytes, was recently shown to form octameric transmembrane pores. We have employed a combination of experiments and models spanning length scales from the atomistic to the cellular level in order to elucidate the microbicidal mechanism of protegrin. Comparison of the modeling and experimental data suggests that approximately 10-100 protegrin pores are necessary to explain the observed rates of potassium leakage and Escherichia coli death in exponential-phase bacteria. The kinetics of viability loss suggest that bacterial death results largely from uncontrolled ion exchange processes and decay of transmembrane potential. However, ion exchange processes alone cannot account for the experimentally observed cell swelling and osmotic lysis-a redundant ''overkill'' mechanism most likely to occur in locales with high protegrin concentrations. Although our study is limited to protegrin and E. coli, the timeline of events described herein is likely shared by other AMPs that act primarily by permeabilizing microbial membranes. This work provides many of the missing links in describing antimicrobial action, as well as providing a quantitative connection between several previous experimental and simulation studies of protegrin.

Engineering Antimicrobial Peptides with Improved Antimicrobial and Hemolytic Activities

“…Widespread use of antibiotics and infiltration of antibiotics into the food chain have promoted the enormous and growing threat of bacterial pathogens that have developed multidrug resistance (MDR) to almost all available antibiotics due to natural evolution, consequently causing many human infectious diseases such as urinary tract infections, tuberculosis, gastroenteritis, pneumonia, and wound infections. − Traditional antimicrobial drugs mainly consist of antibiotics and antimicrobial peptides (AMPs). A large number of antibiotics has been contemplated and widely used as FDA-approved drugs such as penicillins, polymyxins, quinolones, tetracylines, and sufonamides. , But, conventional antibiotics often suffer from the limited activity to kill both Gram-positive and Gram-negative pathogens and undesirable side effects.…”

“…On the other hand, naturally occurring AMPs produced by mammals and plants offer many advantages as a next generation of “nature antibiotics,” − including broader spectrum activity to kill both Gram-positive and Gram-negative bacteria, fungi, and parasites (even clinically common methicillin-resistant S. aureus and vancomycin-resistant Enterococcus); a lower toxicity to host eukaryotic cells; and a synergistic and benign effect with conventional antibiotics. , Meanwhile, many bacteria have also developed resistance to almost all available antibiotics and AMPs to some degree via natural evolution. ,, Undoubtedly, there is an urgent need for the development of new effective AMPs to fight against accelerating bacteria MDR by natural evolution.…”

Antifungal Peptides and Proteins to Control Toxigenic Fungi and Mycotoxin Biosynthesis

“…Peptide analogs of natural AMPs have been synthesized with substituted, deleted, or extended amino acids. Synthetic analogs have been produced through the modification of amino acid sequence, either by shortening the sequence to determine minimal antimicrobial motifs, or by extending peptide length, even by fusion of fragments from different peptides [73]. These approaches, mainly directed to improve the antifungal activity, reduce toxicity to non-target cells and increase stability against degradation; additionally, they have contributed substantially to increasing the number and diversity of known AMPs [37,[74][75][76].…”

“…With respect to large scale production of AMPs, chemical synthesis is still too expensive, and the cost is not always affordable [73,113]. Moreover, production and pu-rification of antifungal AMPs from natural sources have several limits, e.g., low peptide amounts [113].…”