Development of Antimicrobial Peptides as Therapeutic Agents

Abstract

Classical antibiotics work by inhibiting bacterial cell wall synthesis, protein synthesis, DNA (deoxyribonucleic acid) replication, or by modifying metabolism. Bacteria can resist antibiotics as a result of chromosomal changes (mutation or inductive expression of a latent chromosomal gene) or the exchange of genetic material via plasmids and transposons. As this chapter will discuss, antibiotics are rendered inactive by three major mechanisms: (1) antibiotic inactivation by destruction or modification, (2) prevention of access of the antibiotic to the target, and (3) alteration of the target site of the antibiotic. Bacteria have a remarkable ability to overcome each new reagent synthesized as a potential classical antibiotic. Consequently, the current priority is the development of alternative drugs and/or the isolation of native molecules that would allow the consistent and proper control of pathogen‐caused diseases.

De Novo Designed Amphipathic α-Helical Antimicrobial Peptides Incorporating Dab and Dap Residues on the Polar Face To Treat the Gram-Negative Pathogen, Acinetobacter baumannii

“…The amphipathicity values of our AMPs are similar to those observed for native AMPs in the length of 22–27 residues (see review by Hodges et al, 2012). 16 In summary, both amphipathicity and the inducible α -helical structure play a critical role in providing AMPs with the desired properties.…”

“Specificity Determinants” Improve Therapeutic Indices of Two Antimicrobial Peptides Piscidin 1 and Dermaseptin S4 Against the Gram-negative Pathogens Acinetobacter baumannii and Pseudomonas aeruginosa

“…Hemolysis of human red blood cells is commonly used for in vitro assessment of AMP toxicity to normal cells. Many variations of this assay exist and inconsistency in red blood cells source, peptide exposure time and reporting of peptide concentrations impede comparison of AMP toxicity [ 57 ]. The length of time erythrocytes are exposed to AMPs during the hemolysis assay is the least standardized parameter of the method and the most commonly cited times are 30 min [ 58 , 59 , 60 ] and 1 hour [ 33 , 61 , 62 , 63 ].…”

Rational Design of α‐Helical Antimicrobial Peptides to Target Gram‐negative Pathogens, Acinetobacter baumannii and Pseudomonas aeruginosa: Utilization of Charge, ‘Specificity Determinants,’ Total Hydrophobicity, Hydrophobe Type and Location as Design Parameters to Improve the Therapeutic Ratio

“…Cationic AMPs of the α‐helical class have two unique features: a net positive charge of at least +2 and an amphipathic character, with a non‐polar face and a polar/charged face (6). In our recent review of α‐helical AMPs, we found that the vast majority of peptides contain between 3 and 10 positively charged residues with a positive charge density of 1–3 positively charged residues for every 10 residues in the peptide (7). The largest number of amphipathic α‐helical AMPs are in the range of 22–27 residues in length (7).…”

“…In our recent review of α‐helical AMPs, we found that the vast majority of peptides contain between 3 and 10 positively charged residues with a positive charge density of 1–3 positively charged residues for every 10 residues in the peptide (7). The largest number of amphipathic α‐helical AMPs are in the range of 22–27 residues in length (7). Also, it is thought that the development of resistance is considerably reduced with membrane‐active peptides whose sole target is the cytoplasmic membrane and whose interactions with membrane components are non‐specific.…”