Antimicrobial peptides
[2] Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.
Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure.
[4][5][6] The secondary structures of these molecules follow 4 themes, including i) α-helical, ii) β-stranded due to the presence of 2 or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended.
Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by ‘barrel-stave’, ‘carpet’ or ‘toroidal-pore’ mechanisms.
[17] This implies that being AMPs with anti-gram-negative bacterial activities may prefer or even require strong amphipathicity and net positive charge.
[citation needed] In addition to killing bacteria directly they have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection, including the ability to alter host gene expression, act as chemokines and/or induce chemokine production, inhibiting lipopolysaccharide induced pro-inflammatory cytokine production, promoting wound healing, and modulating the responses of dendritic cells and cells of the adaptive immune response.
The peptide is being examined in a Phase III clinical trial by Soligenix (SGNX) to ascertain if it can assist in repair of radiation-induced damage to oral mucosa arising during cancer radiotherapy of the head and neck.
[25][26] Human defensins have been thought to act through a similar mechanism, targeting cell membrane lipids as part of their function.
In fact human beta-defensin 2 have now been shown to kill the pathogenic fungi Candida albicans through interactions with specific phospholipids.
[28] Antimicrobial peptides have been used as therapeutic agents; their use is generally limited to intravenous administration or topical applications due to their short half-lives.
[33] Cecropin A can destroy planktonic and sessile biofilm-forming uropathogenic E. coli (UPEC) cells, either alone or when combined with the antibiotic nalidixic acid, synergistically clearing infection in vivo (in the insect host Galleria mellonella) without off-target cytotoxicity.
The multi-target mechanism of action involves outer membrane permeabilization followed by biofilm disruption triggered by the inhibition of efflux pump activity and interactions with extracellular and intracellular nucleic acids.
[34] Recently there has been some research to identify potential antimicrobial peptides from prokaryotes,[35] aquatic organisms such as fish,[36][37] and shellfish,[38] and monotremes such as echidnas.
[49] Dual polarisation interferometry has been used in vitro to study and quantify the association to headgroup, insertion into the bilayer, pore formation and eventual disruption of the membrane.
For example, attempts have been made to modify and optimize the physicochemical parameters of the peptides to control the selectivities, including net charge, helicity, hydrophobicity per residue (H), hydrophobic moment (μ) and the angle subtended by the positively charged polar helix face (Φ).
While simple in concept, it has taken many decades of work to accomplish the difficult hurdle of transporting antimicrobials across the cell membranes of pathogens.
Lessons learned from the successes and failures of siderophore-conjugate drugs evaluated during the development of novel agents using the ‘Trojan horse’ approach have been reviewed.
CAMP contains AMP prediction, feature calculator, BLAST search, ClustalW, VAST, PRATT, Helical wheel etc.
dbAMP:[75] Provides an online platform for exploring antimicrobial peptides with functional activities and physicochemical properties on transcriptome and proteome data.
