We are entering the Post-Antibiotic Era, a time when antibiotics are losing their almost magical effectiveness as bacteria become resistant to clinically useful drugs. Medicine is in desperate need of alternative therapies for infectious diseases.
Naturally-occurring antimicrobial compounds offer potentially desirable prospects in these times. Peptides (short chains of amino acids) with antimicrobial activities are part of the innate immunity of almost all living organisms, protecting them from infection and competition.
This includes bacteria, plants, and animals up to mammals. As a result, an enormous diversity of antimicrobial peptides exists, both in terms of both structure and inactivity. Individual peptides may be active against bacteria, viruses, fungi, or other types of microorganisms.
Typical antimicrobial peptides are between 12 and 50 amino acids in length. Although they are very diverse in structure, most include two or more positively charged residues such as arginine, lysine or histidine, and usually over 50% hydrophobic amino acids.
These peptides exert their antimicrobial effects in a variety of ways, including membrane permeabilization and by interfering with metabolism by targeting many different cytoplasmic components. In many cases, the antimicrobial activity has been identified by bioassay, and the exact mechanism of killing is not known.
Also, interact with the Immune system
In addition to killing microorganisms directly, such peptides may also interact with the immune system. Although this is undoubtedly a valuable biological property, from replacing antibiotics, directly bacteriocidal peptides are the most exciting type.
One of the most exciting things about antimicrobial peptides is that in contrast to conventional antibiotics, they generally have a broad range of activity, but do not appear to induce resistance. Part of the reason for this is that they are mostly bacteriocidal as opposed to bacteriostatic and require a short contact time to induce killing.
In other words, organisms that encounter sufficient concentrations of these compounds are usually killed before resistance has time to develop. Consequently, there has been much interest in searching for these agents in recent years. ANTIMIC, an online database of antimicrobial sequences, contains nearly 2000 peptide sequences known to have some antimicrobial activity (Nucleic Acids Res 2004 32: D586-9).
A considerable number of peptides are currently being investigated in clinical trials, although none have yet found their way into widespread use. Along with many lower animals, amphibian skin is one of the most generous sources of these peptides.
Several novel molecules have been discovered, and these serve to protect amphibians, living in a soup of potential pathogens, from infection (Antimicrobial peptides from amphibian skin: an expanding scenario. Curr Opin Chem Biol. 2002 6: 799-804).
An example of this is a recent report of Ranalexin, a 20-residue antimicrobial peptide isolated from the skin of the American bullfrog Rana catesbeiana, as a treatment for the antibiotic-resistant “superbug” MRSA. Of course, in addition to using naturally occurring peptides directly as drugs, they can also serve as templates for the design of novel synthetic antimicrobial compounds.
— Elena Conti (@Elen_biota) September 9, 2019
As these are quite potent molecules, they usually occur in only vanishingly small quantities in their natural hosts. Consequently, it is generally difficult to purify enough of the peptide even for analysis, let alone for widespread clinical use.
As the clinical potential of these peptides becomes more apparent, attention is turning to better production methods such as heterologous microbial expression systems. Such methods allow the compounds to be produced in useful quantities by convenient organisms such as Escherichia coli (Recombinant production of antimicrobial peptides in heterologous microbial systems. Biotechnol Appl Biochem. 2007 47: 1-9).
Hopefully, these naturally occurring compounds and artificial derivatives based on them will be able to assist in the fight against the rise of antibiotic-resistant superbugs. While you’re here, read our article on Vitamin B12 here.