Antimicrobial Peptides – an alternate for drug resistance

Antimicrobial peptides are oligopeptides having small molecular weight protein molecules produced by various organisms and are involved in their natural defense mechanism.

Antimicrobial Peptides - an alternate for drug resistance

They are found to have broad spectrum antimicrobial effect against variety of viruses, bacteria and fungi as well as against those pathogens that have acquired resistance against conventional drugs. In addition they possess low tendency for developing resistance in pathogens because of their unique mode of action.

History and origin

The field of antimicrobial peptide research was started in 1980’s after Hans Boman stated that the silk moths contain peptides (cecropins) in its immune system having broad-spectrum antimicrobial activity. Just after that some more AMPs were identified by other scientists too.

For example, Shunji Natori discovered sarcotoxins from larvae of fly; Robert Lehrer discovered defensins from mammalian macrophages and Michael Zasloff discovered magainins from the skin of the frog Xenopus laevis.

The discovery of first antimicrobial peptide dates back to 1939. It was extracted by Dubos from a soil Bacillus strain. That peptide showed effectiveness against pneumococci infection of mice. After that various sources were used for the extraction of antimicrobial peptides.

Defensin is reported to be the first animal-originated AMP. It was isolated from leukocytes of rabbit in 1956. Meanwhile bombinin was isolated from epithelia and lactoferrin from cow milk. It was also found that human leukocytes also contain AMPs in their lysosomes.

Types of antimicrobial peptides

Antimicrobial peptides (AMPs) are classified in various groups on the basis of their structural differences. They include:

α-Helical AMPs

This includes the linear peptides having α helical structure. This is the largest and most studied group of AMPs. They are either amphipathic and absorb through the membrane surface or possess selective toxicity for microbes. It includes cecropin, magainin and temporins etc.

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Cysteine rich AMPs

These are 30 amino acid long peptides which are rich in cysteine. They include defensins and are present in a variety of organisms. They are mostly present in the form of dimers.

β-Sheet AMPs

β-Sheet AMPs are cyclic peptides having disulfide bonds. Defensins are the most common AMPs in the form of β-Sheet. Their cyclic structure also possesses antimicrobial effect. They show antimicrobial effect by perturbation of lipid bilayers and this activity is found to be largely associated with the presence of cysteine residues.

AMPs rich in regular amino acids

These antimicrobial peptides are made up of a large numbers of regular amino. The example includes a peptide peptide histatin which is produced from saliva. It shows antifungal effect by crossing the yeast cell membrane and targeting the mitochondria.

AMPs with rare modified amino acids

This includes the group of AMPs that are composed of some rare amino acids. The example includes lantibiotic produced by Lactococcus lactis. It consists of ring structures that are enclosed by thioether bond. This class of AMPs show a considerable potential to be used against infectious diseases.

Mode of action

Membrane dysfunction

Studies have shown that some antimicrobial peptides cause membrane depolarization leading to ion loss and disturbing metabolite gradient. This in return disrupts some very important functions such as respiration leading to microbial cell death.

Inhibition of cell wall synthesis

Cell wall is an important structure of cell responsible to give shape and protect the cell against lysis. Inhibition of synthesis of cell wall components like peptidoglycan, chitin and some other macromolecular is also an important mechanism of antimicrobial peptide action.

Inhibition of nucleic acid and protein synthesis

Though disruption of cell membrane or cell wall leads to cell death but in certain cases even after that the cell remains viable after a long period. Under that case inhibition of nucleic acid or protein synthesis is essential for cell death.

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There are certain peptides that selectively inhibit DNA metabolism or protein synthesis. As these peptides have positive change so they actively bonds with negatively charged nucleic acid.

Induction of cell death

There are two different mechanisms of cell death. One is apoptosis which is programed cell death. The other one is necrosis which is unprogrammed or accidental death. An important mechanism of cell death is induction of apoptosis by caspase cascade. Studies have shown that it is promoted in the presence of K+ efflux.

Such type of studies can help in development of anti-tumoral drugs that can assist to prevent the growth of tumor cells.  Certain AMPs have been identified that possess this property. For example magaininis found to induces apoptosis by elevating the level of reactive oxygen species and caspase-3 activity in HL-60 cells, which is a cancer cell line present in acute promyelocytic leukemia.

antimicrobial
Mode of Therapeutic Action by Antimicrobial Peptides.

Therapeutic potential of antimicrobial peptides

Antimicrobial peptides can prove as fascinating therapeutic agent because of their broad spectrum activity, the most important of which is their action against drug-resistant bacteria. Despite of all these benefits AMPs also have some limitations like they are labile. They depend upon the surrounding environment pH and presence of protease or organic compounds.

Other limitations include their toxicity for oral application as well as the cost of production.  Beside all these limitations AMPs are generally considered as less toxic for eukaryotes. There are many methods that are being proposed to overcome these obstacles by the production of synthetic AMPs.

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They include addition of unusual amino acids or modification of the terminal regions. These modifications also protect them from proteolytic degradation. Another way to improve the efficiency of AMPs is the use of some efficient drug delivery system like liposome encapsulation.

This will not only improve their stability but will also reduce their toxicity. In spite of all this one issue still remains that is the cost issue. It can be overcome by construction small peptides with increased antimicrobial activity.

Owing to the therapeutic features of AMPs they can supplement conventional antibiotics. They can also be used in synergy with classical antibiotics. Efforts are also being made to develop AMPs that do not directly cause bacterial death but selectively trigger the body’s defense system without causing inflammation.

Conclusion

The urgent need to obtain new antimicrobials has been driving AMP research. With rapid growth in related knowledge more AMPs may enter clinical tests and treatment in the near feature. However, infection control by AMP is still hindered by several challenges including low specificity, high manufacturer cost, potential toxicity to animal cells, and lack of a robust guideline for rational design.

Thus, there is a need to understand the effects of structural modifications on the physiochemical characteristics of AMPs as well as their target spectrum and activity. Recently, these types of studies have been increasing and computational approaches have been involved in AMP research. These efforts will help to better understand the mode of action of AMPs and predict their activities.

Author: Saman Fatima

Environmentalist and biotechnologist.

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Saman Fatima

Environmentalist and biotechnologist.

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