Department of Biochemistry and Biotechnology, University of Gujrat, Gujrat, Pakistan
Corresponding author details:
Daud Faran Asif
Department of Biochemistry and Biotechnology
University of Gujrat
Gujrat,Pakistan
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© 2020 Asif DF. This is an openaccess article distributed under the terms of the
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Antimicrobial peptides (AMPs); Antibiotics; SAR structure activity relationship
AMPs are polypeptides produced by multicellular organisms. These are produced to protect the host from activity of certain microbes. As AMP provide defense against microbes they are also known as host defense peptides HDPs. AMPs play key role in developing innate immunity [1-4]. AMPs re composed of linear amino acid chain ranging in length up to 50 aminoacids. AMPs have typically cationic amphipathic properties. One side of AMPs is positively charged and other side is hydrophobic in nature. Arginine along with lysine provides positive charge to AMPs [1,2,5,6].
AMPs show activity against a broader range of micro organisms including Gram positive and Gram negative bacteria as well as fungi and viruses [1]. AMPs are effective for bacteria that are resistant to traditional antibiotics i.e MDR bacteria multidrug resistance bacteria [7-9]. Moreover there is less chance that bacteria would get resistant to AMPs. Resistance in bacteria against antibiotics is achieved by inhibition of drug target interaction and modification of drug binding site in target proteins. Genetic pattern of microbes can also be altered by a complex system called sensor transducer response. For example bacteria can alter their gene expression in the presence of AMPs [10]. AMPs possess low propensity to develop resistance due to their unique mode of action. AMPs act directly act on membrane of pathogen. AMPs develope peptide-lipid interactions by their positive side and hydrophobic side [3,11-16].
This characteristic mechanism called membranolytic effect enable AMPS to avoid common resistance mechanism of general antibiotics. AMPs thus receiving great attention as alternative of conventional antiobiotics.
Structure
AMPs are divided into sub groups on the basis of their amino acid in peptide and their structure. These are usually consist of 12-50 amino acid. These AMPs include arginine and lysine as positive charged amino acids and a large proportion of hydrophobic residues. AMPs show antimicrobial activity by targeting membranes or action to cytoplasm (Table 1).
Immunomodulation
In addition to kill bacteria directly AMPs induce innate immunity. It may involve
Animal models indicate that host defence peptides play key role in clearance and prevention of infection (Figure 1).
Structure activity relationships (SAR) of AMPs
AMPs are of four types β-sheet, extended, α-helical and loop peptides [1-3,6]. The α-helical are well studied in structure activity relationships. It includes magainin, cecropin, and pexiganan. This group of peptides usually loss its structure in aqueous medium. These AMPs form barrel like bundles in bacterial cell membranes and these transmembrane aggregate line amphipathic pores. Many α-helical AMPs can target bacterial membranes by forming carpet like aggregates of peptides. Some α-helical form toroidal pores to distort the bacterial membranes [1-7,9,11].
The β-sheet AMPS are stabilized by S-S bridges and usually form rigid structure. These include β-defensins, and protegrin. Most of β-sheet AMPs disrupt bacterial membranes by tilting or inserting into lipid bilayer to form toroidal pores and hydrophobic regions of peptides interact with polar head groups of membranes [3].
The extended AMPs contain some aminoacids in more amount such as proline, arginine, tryptophan and histidine. Indolicidin is a tryptophan and proline rich peptide that falls in extended type category. Bac5 and Bac7 are proline and arginine rich peptides these peptides target the cell membrane [17,18]. Many extended AMPs are not effective against membranes of microbes but they can show antimicrobial activity by interacting with bacterial proteins inside [3]. Some extended AMPs e.g indolicidin show membrane activity and act directly on membranes of pathogens.
The loop AMPs form a loop formation with the help of I sulphide bonds. For example bactenecin [17,18].
Understanding structure activity relationships SAR of AMPs is crucial for development of novel peptides that have better properties than natural peptides.Pexiganan also called as MSI-78 , a synthetic derivative of magainin is one of best understood peptide in terms of drug development [19,20]. Pexiganan is currently on clinical trials for the treatment of diabetic foot ulcer infections [4,20,21]. 3D structure of pexiganan determined by NMR (nuclear magnetic resonance) revealed that peptide forms dimeric anti parallel structure in the presence of membrane mimetics [22-30]. Structure of peptide and the orientation of peptide in membrane plays key role in understanding the mode of action of peptide [22].
Antimicrobial peptides as therapeutic agents
AMPs got attention to study as new generation antibiotics because of their broad spectrum activity against microbes and MDR bacteria. Since the isolation of megainins from frog skin their have been many attempts to synthesis antibiotics from natural AMPs [31]. Despite the efforts currently there is no AMP agent approved by FDA [4,32,33-37]. Although AMPs have certain advantages over conventional antibiotics they have certain limitations. The natural AMPs are liable depending upon surrounding conditions such as presence of proteases. change in pH and potential toxicity [2]. Moreover high cost of peptide production make it less economical. In order to overcome these problems many methods have been presented. For instance introduction on unusual amino acids in peptides to prevent its degradation by proteases. Stability of peptides can also be improved by introduction of amide or acetyl groups at terminal regions of peptides. Use of efficient drug delivery vehicles such a liposomes can reduce the potential toxicity [38,39]. High production cost is one of major issues for peptide production roughly cost estimated is $50-$400 per 1 gram of amino acid [7]. In order to sort the cost issue short peptides can by synthesized that retain the potential to act as antimicrobial agent. There have been several examples of peptide engineering to reduce the peptide size with retained anti microbial activity. For example thegaegurin 5 (GGN5N11) can retain the potential to kill microbes just by a single substitution of tryptophanylat amphipathic [29,30].
Classification of AMPs
Based on mode of action and target AMPs can be divided into following catagories (Table 2)
Important Physiochemical Properties of AMPs
Following are important properties of AMPs
AMP Modifications
Most of AMPs are produced directly in their active form in order to enhance their stability certain modifications can be done. These are as follow
Small Peptides in Drug Development
hLF1-11 (Human Lactoferrin 1-11): Lactoferin is an iron binding glycoprotein that plays a role in innate defense system. LF can not only bind Fe3+ but target the bacterial membrane that enable LF to act against microbes [40-43]. The synthetic hLF-11 (GRRRRSVQWCA) is LF derivative. It shows activity against microbes including Gram positive as well as Gram negative bacteria. The synthetic peptide is also effective against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii strains [43–45]. Its also effective against fluconazoleresistant C. albicans when used in combination with fluconazole [46].
3D structure of several LF derived peptides in membrane mimetic environment have been studied by NMP spectroscopy [47-50]. The confirmation of hLF1-11 varied depending upon environmental conditions [43]. Molecular dynamics MD results suggested that this peptide should be categorized as loop peptide.
The safety of hFL1-11 have been tested in haemato poietic stem cell transplantation (HSCT) recipients and healthy persons [43,51]. Intra venous injection of hFL1-11 were safe and tolerable in both healthy and HSCT recipient. While some adverse events were reported.
(CKPV)2 Peptide (α-MSH Derivative, also Named CZEN-002): The α-melanocyte stimulating hormone (SYSMEHFRWGKPV) is a neuro peptide showing antimicrobial and anti inflammatory activity [52-54]. It’s studied that α-MSH peptides are effective against Candida albicans and their mode of action is different from other natural AMPs. This activity of peptide is caused by increased cyclic adenosine monophosphate (cAMP) in the C. albicans cells [55], whereas most of AMPs kills microbes by direct interaction with their membranes. It is suggested that cAMP-mediated modulation is essential for gene expression in C. albicans and the cAMP activating effect of α-MSH interferes with the cAMP-mediated signaling pathway [56,57].
The C-terminal tripeptide (α-MSH11-13; KPV) also has antiinflammatory and antimicrobial activities same as shown by α-MSH [55,58]. The synthetic peptide (CKPV)2, also called as CZEN002, was designed by modifying KPV (α-MSH11-13) peptide. This peptide is classified as loop peptide, it is a dimeric octamer consisting of two KPV units connected by cysteine-cysteine linker. The CKPV2 peptide show effective candidacidal activity against C. krusei and C. glabrata that are MDR strains [59-62]. This peptide also exerts anti inflammatory as well as candidacidal effect [60-62]. CKPV2 due to smaller size and simple sequence is regarded as effective agent for development of candidacidal and anti-inflammatory drugs. CKPV2 is being currently studied in clinical trials for treatment of vulvovaginal candidiasis [4]. CKPV2 adopts a symmetric dimer with an extended backbone structure, which resembles the α-MSH peptide [63]. The overall conformation of CKPV2 showed a β-turn like fold, which may be related to the higher activity of CKPV2 than KPV monomer [59].
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