Multitalented Synthetic Antimicrobial Peptides and Their Antibacterial, Antifungal and Antiviral Mechanisms

Abstract

Despite the great strides in healthcare during the last century, some challenges still remained unanswered. The development of multi-drug resistant bacteria, the alarming growth of fungal infections, the emerging/re-emerging of viral diseases are yet a worldwide threat. Since the discovery of natural antimicrobial peptides able to broadly hit several pathogens, peptide-based therapeutics have been under the lenses of the researchers. This review aims to focus on synthetic peptides and elucidate their multifaceted mechanisms of action as antiviral, antibacterial and antifungal agents. Antimicrobial peptides generally affect highly preserved structures, e.g., the phospholipid membrane via pore formation or other constitutive targets like peptidoglycans in Gram-negative and Gram-positive bacteria, and glucan in the fungal cell wall. Additionally, some peptides are particularly active on biofilm destabilizing the microbial communities. They can also act intracellularly, e.g., on protein biosynthesis or DNA replication. Their intracellular properties are extended upon viral infection since peptides can influence several steps along the virus life cycle starting from viral receptor-cell interaction to the budding. Besides their mode of action, improvements in manufacturing to increase their half-life and performances are also taken into consideration together with advantages and impairments in the clinical usage. Thus far, the progress of new synthetic peptide-based approaches is making them a promising tool to counteract emerging infections.

Antifungal Activity of the Frog Skin Peptide Temporin G and Its Effect on Candida albicans Virulence Factors

“…The available antifungals are not efficient in eradicating biofilm-related infections [ 59 , 60 , 61 ], and the emergence of multi-resistant fungal strains [ 62 , 63 , 64 ] has become a serious health concern in this century [ 65 , 66 ]. In recent years, the search for new therapeutic approaches with different targets or mechanisms of action has been constantly evolving [ 64 , 67 ], and several authors have proposed AMPs, and temporins, as promising scaffolds for the development of new antifungal compounds [ 13 , 14 , 16 , 23 , 24 , 25 , 68 ]. Our group and others have described the antifungal activity of temporins L and B [ 69 , 70 ].…”

“…They are present in both prokaryotic and eukaryotic organisms and are critical components of the innate immunity, with the function of protecting the host against a wide range of microorganisms, including bacteria, fungi, protozoa, and viruses [ 9 , 11 , 12 ]. Many works have demonstrated the effectiveness of AMPs against a broad spectrum of microbial pathogens [ 13 , 14 , 15 ]. Among the AMPs are found temporins, short peptides initially isolated from the skin secretion of the European red frog Rana temporaria [ 16 , 17 , 18 , 19 , 20 , 21 ] and subsequently also identified in other ranid frogs of both North American and Eurasian origin [ 22 ].…”

Compartmentalized Innate Immune Response of Human Fetal Membranes against Escherichia coli Choriodecidual Infection

“…Our results agree with others showing a synergistic effect of HBDs and LL-37 against E. coli [ 58 ]. This may be explained considering that AMP often act on different bacterial targets and with diverse mechanisms of action: (i) AMP group and bind to the bacterial wall or membrane, form pores, keep them open, and prevent their repair; (ii) AMP can also bind to the bacterial wall, preventing peptidoglycan elongation; (iii) some AMP can be endocytosed or directly penetrate into the bacterial cytoplasm and affect several enzymes involved in vital processes (such as matrix metalloproteases, which are essential in microbial cell growth and homeostasis); (iv) some AMP present a high binding affinity for DNA and RNA and can act as inhibitors of nucleic acid biosynthesis, which disrupts bacterial replication and messenger transcription; (v) additionally, they can bind to several components of the translation machinery and inhibit protein translation and protein folding or lead to protein degradation; and vi) they inhibit the formation of biofilms [ 59 , 60 ]. In addition to the bacterial targets, AMP can also bind to host targets, and regulate their immune response: (i) AMP reduce the host inflammatory reaction caused by endotoxins; (ii) favor mast cell degranulation and histamine release, enhancing splenocyte and lymphocyte production of Th1 and Th2 cytokines; (iii) AMP have been shown to increase the production of chemokines released from immune and epithelial cells, favoring the chemoattraction of monocytes, neutrophils, mast cells, naïve T cells, CD8 T cells, immature dendritic cells, and endothelial cells to fight against infection [ 60 , 61 ].…”

In Vitro & In Vivo Studies on Identifying and Designing Temporin-1CEh from the Skin Secretion of Rana chensinensis as the Optimised Antibacterial Prototype Drug

“…Another assumption is that the initial interaction of AMPs approaching Gram-positive bacteria and Gram-negative bacteria is different because of the differences of both membrane structures [ 39 ]. The electrostatic interactions between cationic AMPs and anionic LPS molecules, as well as the consumption to disrupt both outer and cytoplasmic membranes, weakened the antimicrobial activity of the peptides against Gram-negative bacteria [ 5 , 40 ].…”