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- Dhayalini Yoginthran
Antibiotic resistance is something that has been growing in the world, some might even say that we are entering or have already entered a post antibiotic world. It is currently one of the superior concerns in the 21st century, especially in regards to pathogenic microorganisms. Throughout the years, research had allowed for the development of first line antibiotics that were efficacious against infections plaguing the population. Due to resistance build up towards first line agents, second line agents were then used to treat infections, which usually have a broad spectrum in treatment. In some cases pathogens have also acquired resistance towards multiple drugs, one such example would be Staphylococcus aureus (Zainnudin and Dale, 1990).
Antimicrobial peptides (AMPs) are substances produced by animals, bacteria and plants. They are also known as host defence peptides and are a part of the non-specific immune system. Differences between eukaryotes and prokaryotes show the potential of targeted therapy with the use of AMPs . They are dynamic and are of broad spectrum and have shown plausible evidence that they may be used as a new therapeutic agent. AMPs are quite small, have various sequences and lengths. They are also known to be cationic and amphipathic (Hultmark, 2003). They have shown considerable bactericidal activity against both Gram positive and Gram negative strains of bacteria, Mycobacterium tuberculosis, malignant cells as well as viruses that are enveloped (Reddy et al., 2004). AMPs work by the interaction with the membrane of the potential pathogen thus leads to the perturbation of said membrane. The peptide is then inserted into the bilayer of the membrane that causes the displacement of the lipids. The perturbation and the displacement actions render it easy for the peptide to be translocation into the intracellular target of the pathogen.
AMPs are usually derived from coding sequences in a gene, databases of known AMPs have been curated to hold information of AMPs as well as to provide tools to predict possible AMPs that are found in genomes (Fjell et al., 2007). The Antimicrobial Peptide database (APD) is one of the major resource for antimicrobial peptide sequences that have been curated. AMPs from various phylogenetic kingdoms are available, making the prediction of models based on qualitative and quantitative activity easier. In order to bring the development of AMPs into light, certain objectives are to be met. An AMP must be active against the pathogen in which it is targeted against and must have a high therapeutic index. In order to look for a suitable AMP that can act as a broad spectrum antibiotic. A method will be explained to show the screening process to look for one such AMP.
The method would be to employ template based studies. A template AMP will be used to look for peptides that have better antimicrobial activity and also is reduced in toxicity by altering amino acid sequences. In order to elucidate positions of amino acids that are important in antimicrobial activity, a single amino acid in the peptide will be changed, and hence the changes will be studied. Template AMPs that could be used for this would be lactoferrin or magainin. The variety of peptides are designed based on the amphiphilicity and charge of the AMPs and their role in antimicrobial activity. It will be possible to synthesis peptides using a high throughput approach of arrays that is done together with a speedy luminescence assay to portray bactericidal activity. This would lead to us being able to perform a complete substitution method to study the amino acid changes in the desired peptide. Several substitution studies that have been performed have shown that the activity shown by the substituted amino acids differ with regards to the template AMP utilised (Schneider et al., 1995). A linguistic model shall be used to pinpoint patterns in natural peptides (Loose et al., 2006). It is possible that the novel peptide that is constructed based on this will show superiority against models that are generated based on the random shuffling of amino acid sequences. Functionally important patterns of amino acids will be found using this linguistic model. In a previous study conducted by Loose et al (2006), 4 out of 40 designed peptides showcased activity against E. coli and B. cereus at an acceptable concentration.
In order to achieve specificity against the membrane of the pathogen, amino acid residues that contain a positive charge is used on the non-polar side of amphiphatic α‑helical AMPs to further strengthen the discrepancy of the peptide when it has to select against prokaryotic and eukaryotic membranes. It is also possible to increase the therapeutic index of the modelled peptide by altering the residues on the known peptide used. It has been demonstrated in a study that computer based drug design has shown that both the haemolytic activity and the therapeutic index has been improved without reducing the antimicrobial activity. In order to find relevant antimicrobial activity, the screening of the AMP should be done against pathogens that are known to cause severe (and possibly fatal) infections.
Since the dawn of the new millennia, approximately 20 new antibiotics have been marketed with even more being in various phases of clinical studies. AMPs have also been designed are in clinical trials, with some of the AMPs showing promise based on the trial results such as AMP hLF1–11 based on lactoferrin and Pexiganan155 based on magainin. There are also AMPs that have failed at the clinical stage, that are owed to several factors. These factors might play a part during the development of this AMP but there are ways to overcome it. One possible problem in the synthesis of this AMP would be the cost of goods required. To reduce that, it is possible to engineer smaller peptides and to utilise approaches that have already been known to give highly potent broad range antibiotics that are able to work in animals. Proteolytic degradation is also another potential problem with designing this AMP. To overcome this problem, it is best to use d-amino acids or artificial analogues of amino acids as well as mimetics that contain a distinct backbone structure. (Choudhary and Raines, 2011). The main issue that poses a problem with the design of this AMP would be toxicity. In order to overcome it, various sequences that are highly active should be created and should be tested for the toxicity or lack of it in animals. Another option would be to use productions that are able to mask the peptide (e.g liposomal formula) until it reaches the target (Desai et al., 2002). The haemolytic toxicity of AMPs are a routine investigation that is performed in the process of drug design. In order to better the algorithms used in designing the AMP, it is of extreme importance that computational prediction of toxicology would be require. Especially in preclinical stages where the toxicological end point of the designed AMP must be identified. Due to there not being sufficient data regarding standardized toxicological data that is specific towards AMPs, machine learning and alerting tools can be used in this aspect of AMP drug design. Multidimensional techniques used in designing have been optimized to be used in combinatorial drug discovery (Fischer et al., 2009). Peptide design that utilises computers would definitely benefit from this. With the advancement of multidimensional techniques, in silico pharmacology that is also used in the design of this AMP would benefit. This AMP and the method used to design it would benefit from studies that have been done previously on natural peptides. Based on previous studies, the disruption of the secondary structure or the usage and modification of the type of amino acid replaced (d-amino acid) has shown that the secondary structure preferred and the biological activity exhibited are not mutually exclusive. In the problem that might occur with the haemolytic activity of this AMO, methylation can be performed without affecting the secondary structure of the AMP as shown in the design of cecropin A–melittin-derived helical AMP (Díaz et al., 2011). The experiments done has shown that the molecular structure can be proportionate towards its antimicrobial activity.
Based on the method utilised above, it is possible for an AMP that has a broad spectrum to be designed and developed, if the criteria needed is met. The possible problems that may occur in the designing of the drug has been discusses and the solutions stated. Designing an AMP will be the hallmark of modern medicine with regards to antimicrobials. As the world enters a post antibiotic era, every avenue should be scoured to produce a cure, and AMPs seem to be a very realistic approach.
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