Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence alternatives are being explored to combat resistance. Antimicrobial peptides (AMPs) have shown great promise, because use of AMPs leads bacteria to develop no or low resistance. In this review, we discuss the diversity, history and the various mechanisms of action of AMPs. Although many AMPs have reached clinical trials, to date not many have been approved by the US Food and Drug Administration (FDA) due to issues with toxicity, protease cleavage and short half-life. Some of the recent strategies developed to improve the activity and biocompatibility of AMPs, such as chemical modifications and the use of delivery systems, are also reviewed in this article.

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Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo

Alarming data about increasing resistance to conventional antibiotics are reported, while at the same time the development of new antibiotics is stagnating. Skin and soft tissue infections (SSTIs) are mainly caused by the so called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) which belong to the most recalcitrant bacteria and are resistant to almost all common antibiotics. S. aureus and P. aeruginosa are the most frequent pathogens isolated from chronic wounds and increasing resistance to topical antibiotics has become a major issue. Therefore, new treatment options are urgently needed. In recent years, research focused on the development of synthetic antimicrobial peptides (AMPs) with lower toxicity and improved activity compared to their endogenous counterparts. AMPs appear to be promising therapeutic options for the treatment of SSTIs and wounds as they show a broad spectrum of antimicrobial activity, low resistance rates and display pivotal immunomodulatory as well as wound healing promoting activities such as induction of cell migration and proliferation and angiogenesis. In this review, we evaluate the potential of AMPs for the treatment of bacterial SSTIs and wounds and provide an overview of the mechanisms of actions of AMPs that contribute to combat skin infections and to improve wound healing. Bacteria growing in biofilms are more resistant to conventional antibiotics than their planktonic counterparts due to limited biofilm penetration and distinct metabolic and physiological functions, and often result in chronification of infections and wounds. Thus, we further discuss the feasibility of AMPs as anti-biofilm agents. Finally, we highlight perspectives for future therapies and which issues remain to bring AMPs successfully to the market.

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Antimicrobial Peptides and Their Therapeutic Potential for Bacterial Skin Infections and Wounds.

The discovery of antibiotics marked a golden age in the revolution of human medicine. However, decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevitable if stringent measures are not adopted to curb the rapid emergence and spread of multidrug resistance and the indiscriminate use of antibiotics. In hospital settings, multidrug resistant (MDR) pathogens, including carbapenem-resistant Pseudomonas aeruginosa, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and extended-spectrum β-lactamases (ESBL) bearing Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae are amongst the most problematic due to the paucity of treatment options, increased hospital stay, and exorbitant medical costs. Antimicrobial peptides (AMPs) provide an excellent potential strategy for combating these threats. Compared to empirical antibiotics, they show low tendency to select for resistance, rapid killing action, broad-spectrum activity, and extraordinary clinical efficacy against several MDR strains. Therefore, this review highlights multidrug resistance among nosocomial bacterial pathogens and its implications and reiterates the importance of AMPs as next-generation antibiotics for combating MDR superbugs.

Antimicrobial peptides: new hope in the war against multidrug resistance

Biofunctions of antimicrobial peptide-conjugated alginate/hyaluronic acid/collagen wound dressings promote wound healing of a mixed-bacteria-infected wound.

Antibacterial and antifungal activities of phenolic compound-enriched ethyl acetate fraction from Cochlospermum regium (mart. Et. Schr.) Pilger roots: Mechanisms of action and synergism with tannin and gallic acid

Antimicrobial peptides (AMPs) have recently attracted a great deal of attention as promising antibiotic candidates, but some obstacles such as toxicity and high synthesis cost must be addressed before developing them further. For developing short peptides with improved cell selectivity, we designed a series of modified PMAP-36 analogues. Antimicrobial assays showed that decreasing chain length in a certain range retained the high antimicrobial activity of the parental peptide and reduced hemolysis. The 18-mer peptide RI18 exhibited excellent antimicrobial activity against both bacteria and fungi, and its hemolytic activity was observably lower than PMAP-36 and melittin. The selectivity indexes of RI18 against bacteria and fungi were improved approximately 19-fold and 108-fold, respectively, compared to PMAP-36. In addition, serum did not affect the antibacterial activity of RI18 against E. coli but inhibited the antifungal efficiency against C. albicans. Flow cytometry and electron microscopy observation revealed that RI18 killed microbial cells primarily by damaging membrane integrity, leading to whole cell lysis. Taken together, these results suggest that RI18 has potential for further therapeutic research against frequently-encountered bacteria and fungi. Meanwhile, modification of AMPs is a promising strategy for developing novel antimicrobials to overcome drug-resistance.

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Yang Yang

Papers

Antimicrobial activity, improved cell selectivity and mode of action of short PMAP-36-derived peptides against bacteria and Candida