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Antimicrobial Peptides: Therapeutic Potentials

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Antimicrobial Peptides: Therapeutic Potentials Review Antimicrobial peptides: therapeutic potentials Expert Rev. Anti Infect. Ther. 12(12), 1477–1486 (2014) Su-Jin Kang1, The increasing appearance of multidrug-resistant pathogens has created an urgent need for Sung Jean Park2, suitable alternatives to current antibiotics. Antimicrobial peptides (AMPs), which act as Tsogbadrakh defensive weapons against microbes, have received great attention because of broad-spectrum activities, unique action mechanisms and rare antibiotic-resistant variants. Mishig-Ochir3 and 1 Despite desirable characteristics, they have shown limitations in pharmaceutical development Bong-Jin Lee* due to toxicity, stability and manufacturing costs. Because of these drawbacks, only a few 1Research Institute of Pharmaceutical AMPs have been tested in Phase III clinical trials and no AMPs have been approved by the US Sciences, College of Pharmacy, Seoul FDA yet. However, these obstacles could be overcome by well-known methods such as National University, Seoul, 151-742, Korea changing physicochemical characteristics and introducing nonnatural amino acids, acetylation 2College of Pharmacy, Gachon or amidation, as well as modern techniques like molecular targeted AMPs, liposomal University, 534-2 Yeonsu-dong, formulations and drug delivery systems. Thus, the current challenge in this field is to develop Yeonsu-gu, Incheon, Korea 3Department of Biophysics, Faculty of therapeutic AMPs at a reasonable cost as well as to overcome the limitations. Biology, National University of Mongolia, Ullanbaatar, Box-377, KEYWORDS: AMPs in drug development • antimicrobial peptides • limitations of AMPs • multidrug resistance Mongolia • strategies for new therapeutic drug *Author for correspondence: Tel.: +82 2880 7869 Fax: +82 2872 3632 For over 80 years after the discovery of the first methicillin-resistant S. aureus is estimated to be [email protected]. antibiotic penicillin, antibiotics have been con- about 64% more than that of people with sidered as a wonder drug against various infec- infection caused by a nonresistant form. To For personal use only. tions, and the development of many different overcome this issue, new alternatives of antibi- kinds of antibiotics has improved people’s qual- otics, which have different mechanisms of ity of life [1–3]. However, these drugs have been action compared to conventional antibiotics, used so widely and for so long that antibiotics are definitely required [6]. In this regard, one of abuse has raised another concern, which is fre- the promising therapeutics is the natural anti- quent emergence of multidrug-resistant micro- microbial peptides (AMPs) [7–9]. AMPs are organisms. This situation includes overuse not defensive weapons in the animal and plant only in the hospital but also in industrial farm- kingdoms. They show strong antimicrobial ing. Actually, essential human pathogens such activity against a very broad spectrum of micro- as Staphylococcus aureus, Mycobacterium tubercu- organisms, such as gram-negative and gram- losis and Pseudomonas aeruginosa have showed positive bacteria, fungi, parasites and viruses, increased resistance against existing antibiotics, via various mechanisms of action [10]. In addi- and some of them cannot be killed by any of tion to direct effects on microorganisms, AMPs Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Korea University on 12/25/14 the antibiotics at all [4,5]. Despite continuing seem to control the innate and adaptive efforts on combating multidrug resistance, immune responses by raising the accumulation spreading of resistant pathogenic bacteria to of immune cells such as macrophages, lympho- conventional antibiotics has become a major cytes and so on [11]. Moreover, they cancel out global concern. In 2014, WHO’s report on the toxicity of lipopolysaccharide endotoxin global surveillance of antimicrobial resistance from gram-negative bacteria by stimulating using data provided by 114 countries shows angiogenesis [12]. These findings may be related that the very high rate of resistant bacteria such to the altered immune responses by AMPs [13]. as Escherichia coli, Klebsiella pneumoniae, S. Furthermore, they are also capable of removing aureus and M. tuberculosis still is a threat to microorganisms with great resistance to conven- global public health in all WHO regions, result- tional drugs because the microorganisms can be ing in health and economical burden. As an killed by rapid and direct action of example, the death rate of patients with AMPs [2,14–16]. Taken together, AMPs have informahealthcare.com 10.1586/14787210.2014.976613 Ó 2014 Informa UK Ltd ISSN 1478-7210 1477 Review Kang, Park, Mishig-Ochir & Lee WEAK STRONG interaction interaction Eukaryotic membrane Bacterial membrane Cholesterol Zwitterionic Acidic A B phospholipid phospholipid Recruiting and activating Protein folding immune cells C D Protein mRNA DNA Enzymatic activity Figure 1. Mechanisms of action of antimicrobial peptides. Because the composition of the eukaryotic cell membrane and the bacte- rial membrane is different, cationic antimicrobial peptides strongly interact with the bacterial plasma membrane. (A) Toroidal pore model, For personal use only. (B) aggregate model, (C) barrel-stave model and (D) carpet model. After penetrating the bacterial membrane using one of the four mechanisms of action, antimicrobial peptides can inhibit the synthesis of DNA, mRNA and proteins and can inhibit cell wall synthesis, recruitment and activation of immune cells and enzymatic activity. several benefits in the treatment of infections, and development charged surfaces of the microbial membranes within which of AMPs has been considered as a promising strategy for the acidic polymers such as lipopolysaccharide and teichoic acids generation of novel antibiotics. are found [2,20,24] In contrast, positively charged AMPs have dif- ficulty binding to the mammalian cell membrane since the General characteristics of AMPs composition of the mammalian cell membrane is quite differ- Naturally occurring AMPs are short polypeptides of which ent from that of the bacterial membrane. Compared to the lengths in sequences are at most 60 amino acids and typically bacterial membrane, neutral phospholipids such as phosphati- the lengths are between 15 and 40 residues. Almost all of them dylcholine, phosphatidylethanolamine and/or sphingomyelin have a positively charged surface. The number of basic amino are abundant in the mammalian cell membrane [25] as shown Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Korea University on 12/25/14 acids such as Arg, Lys and His is usually in excess of +2 to in FIGURE 1. Upon binding to membranes of pathogens, linear +9 (most commonly +4 to +6) [17]. While AMPs are generally AMPs usually adopt a helical structure with significant confor- unstructured in aqueous solution, a membrane mimetic envi- mational changes. Subsequently, these are attached to the inter- ronment causes AMPs to form a structure and induces signifi- face between the hydrophilic head groups and the fatty acyl cant amphipathicity, which means that hydrophilic residues lie chains of the membrane phospholipids and then form mem- on one side of the peptide and hydrophobic residues lie on the brane pores by oligomerization. The formation of membrane other side [14,18–21]. The selective interaction with the mem- pores, through which the cellular components can be leaked, brane of microorganisms generally depends on the cationic affects the viability of pathogenic bacteria [26]. nature of AMPs, and the perturbation of membrane structures Currently, several complex and controversial mechanisms of by AMPs generally depends on the amphipathic nature of action exist as to how AMPs disrupt the bacterial cell mem- AMPs. The mode of action of AMPs are related to the interac- brane. The four popular models are the toroidal pore model, tion with bacterial cell membranes [22,23]. In the first stage of the aggregate model, the barrel-stave model and the carpet their action, cationic AMPs are diffused to the negatively model [23,27–29]. The toroidal model explains the disruption of 1478 Expert Rev. Anti Infect. Ther. 12(12), (2014) Antimicrobial peptides Review the bacterial membrane as follows: when A B C D the peptides meet the lipid bilayer, they are perpendicularly incorporated into the cell membrane, in which hydrophobic residues of peptides interact with the hydrophobic region of the membrane forming a pore. As the peptides keep curving inward into the membrane, the Figure 2. Four representative structural classes of antimicrobial peptides. pores continuously become larger and (A) a-helical (magainin-2, PDB ID: 2MAG), (B) b-sheet (defensins, PDB ID: 2LXZ), larger, resulting in irreversible membrane (C) extended (indolicidin, PDB ID: 1QXQ) and (D) loop (microcin, PDB ID: 1S7P) peptides. disruption. In the aggregate channel model, the peptides bind to the head groups of phospholipids in the lipid bilayer and are inserted most studied group because the largest population of AMPs dis- into the membrane by randomly aggregating with lipids. covered from the nature adopts a-helical conformation. Aggregation of peptides and lipids resembles micelles and occurs without a particular orientation. These aggregates span a AMPs in drug development wide range of membrane surfaces and provide channels for ion Several AMPs have been successfully developed for pharmaceu- leakage through the membrane. The barrel-stave model empha- tical and commercial
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