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Schematic of membrane disruptive and non-membrane disruptive bacterial killing mechanisms of AMPs Illustration created with BIORENDER.COM.
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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...
Context in source publication
Context 1
... research has been conducted, and is still ongoing, to unveil the MOA of AMPs ( Guilhelmelli et al., 2013;Hancock & Lehrer, 1998;Ulm et al., 2012). Based on their MOA, AMPs can be classified into those that kill through membrane disruptive mechanisms and non-membrane disruptive mechanisms, as illustrated in Figure 3. For the membrane disruptive killing action, AMPs produce microbicidal activity by targeting and disrupting the bacterial plasma-membrane structure, mostly through permeabilization, thus resulting in leakage of intracellular content ( Huang et al., 2010). ...
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Significance
This work showed that a designed cyclic peptide ZY4 exhibits excellent activity against Pseudomonas aeruginosa and Acinetobacter baumannii . ZY4 not only inhibits planktonic growth and biofilm formation but also kills persister cells by permeabilizing bacterial membrane. ZY4 showed low propensity to induce resistance, high stability in...
Antimicrobial peptides have been identified as one of the alternatives to the extensive use of common antibiotics as they show a broad spectrum of activity against human pathogens. Among these is Chionodracine (Cnd), a host-defense peptide isolated from the Antarctic icefish Chionodraco hamatus, which belongs to the family of Piscidins. Previously,...
Citations
... The spread of antimicrobial resistance (AMR) has attained a state of 'global emergency' in the 21st century [1]. The statistics from the World Health Organization (WHO) have warned against the indiscriminate use of conventional antibiotics by humans in healthcare, the food sector, animal husbandry, and agriculture resulting in a high mortality of approximately 10 million deaths worldwide [2,3]. The rising frequency of antibiotic resistance and the emergence of drug-resistant diseases have a significant impact on developing countries' economies [4,5], particularly those with limited healthcare facilities. ...
... The most studied β-sheet peptides are defensins, which are generated by neutrophils, epithelial cells, and macrophages as inactive precursor molecules [123,126]. These AMPs exhibit potent antibacterial action and are found in plants, invertebrates, and vertebrates [3]. Loops and extended-coil structures are included in the third class of AMPs. ...
... These AMPs work against Gram-negative bacteria by disrupting membranes and have anticancer effects as part of their broad-spectrum function [130]. Other significant examples are histatin (human saliva), tritrpticin, and indolicidin, a 13-amino acid peptide with strong antibacterial action [3,130]. ...
The increased prevalence of antibiotic resistance is alarming and has a significant impact on the economies of emerging and underdeveloped nations. The redundancy of antibiotic discovery platforms (ADPs) and injudicious use of conventional antibiotics has severely impacted millions, across the globe. Potent antimicrobials from biological sources have been extensively explored as a ray of hope to counter the growing menace of antibiotic resistance in the population. Antimicrobial peptides (AMPs) are gaining momentum as powerful antimicrobial therapies to combat drug-resistant bacterial strains. The tremendous therapeutic potential of natural and synthesized AMPs as novel and potent antimicrobials is highlighted by their unique mode of action, as exemplified by multiple research initiatives. Recent advances and developments in antimicrobial discovery and research have increased our understanding of the structure, characteristics, and function of AMPs; nevertheless, knowledge gaps still need to be addressed before these therapeutic options can be fully exploited. This thematic article provides a comprehensive insight into the potential of AMPs as potent arsenals to counter drug-resistant pathogens, a historical overview and recent advances, and their efficient production in plants, defining novel upcoming trends in drug discovery and research. The advances in synthetic biology and plant-based expression systems for AMP production have defined new paradigms in the efficient production of potent antimicrobials in plant systems, a prospective approach to countering drug-resistant pathogens.
... AMPs also stimulate invertebrate immune regulation, enhancing the endogenous immune response to protect against microbial threat [5]. Whilst AMPs have gained significant attention as novel, resistance-breaking, antimicrobial agents [6], their key roles in invertebrate innate immunity highlight an unexplored opportunity for the exploitation of AMPs as novel targets for the control of invertebrate pathogens, including nematode parasites. Phylum Nematoda belong to the clade Ecdysozoa which also includes arthropods and tardigrades [7]. ...
Antimicrobial Peptides (AMPs) are key constituents of the invertebrate innate immune system and provide critical protection against microbial threat. Nematodes display diverse life strategies where they are exposed to heterogenous, microbe rich, environments highlighting their need for an innate immune system. Within the Ecdysozoa, arthropod AMPs have been well characterised, however nematode-derived AMP knowledge is limited. In this study the distribution and abundance of putative AMP-encoding genes was examined in 134 nematode genomes providing the most comprehensive profile of AMP candidates within phylum Nematoda. Through genome and transcriptome analyses we reveal that phylum Nematoda is a rich source of putative AMP diversity and demonstrate (i) putative AMP group profiles that are influenced by nematode lifestyle where free-living nematodes appear to display enriched putative AMP profiles relative to parasitic species; (ii) major differences in the putative AMP profiles between nematode clades where Clade 9/V and 10/IV species possess expanded putative AMP repertoires; (iii) AMP groups with highly restricted profiles (e.g. Cecropins and Diapausins) and others [e.g. Nemapores and Glycine Rich Secreted Peptides (GRSPs)] which are more widely distributed; (iv) complexity in the distribution and abundance of CSαβ subgroup members; and (v) that putative AMPs are expressed in host-facing life stages and biofluids of key nematode parasites. These data indicate that phylum Nematoda displays diversity in putative AMPs and underscores the need for functional characterisation to reveal their role and importance to nematode biology and host-nematode-microbiome interactions.
... Antimicrobial peptides have a wide antibacterial spectrum, low molecular weight, high thermal stability, and good water solubility. Current research has focused on molecular structure and improvement, mechanism of action, and other aspects [9]. Because antimicrobial peptides have a special mechanism of action, bacteria cannot easily develop resistance; therefore, they are likely to become new alternatives to conventional small-molecule antibiotics. ...
Background
Recently, researchers have focused on the search for alternatives to conventional antibiotics. Antimicrobial peptides are small bioactive peptides that regulate immune activation and have antibacterial activity with a reduced risk of bacterial resistance. Porcine myeloid antibacterial peptide 37 (PMAP-37) is a small-molecule peptide with broad-spectrum antibacterial activity isolated from pig bone marrow, and PMAP-37(F34-R) is its analogue. In this study, PMAP-37(F34-R) was recombinantly expressed in Pichia pastoris , and the recombinant peptide was further investigated for its antibacterial properties, mechanism and preservative in plums.
Results
To obtain a Pichia pastoris strain expressing PMAP-37(F34-R), we constructed a plasmid expressing recombinant PMAP-37(F34-R) (pPICZα-PMAP-37(F34-R)-A) and introduced it into Pichia pastoris . Finally, we obtained a highly active recombinant peptide, PMAP-37(F34-R), which inhibited the activity of both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration is 0.12–0.24 µg/mL, and it can destroy the integrity of the cell membrane, leading to cell lysis. It has good stability and is not easily affected by the external environment. Hemolysis experiments showed that 0.06 µg/mL-0.36 µg/mL PMAP-37(F34-R) had lower hemolysis ability to mammalian cells, and the hemolysis rate was below 1.5%. Additionally, 0.36 µg/mL PMAP-37(F34-R) showed a good preservative effect in plums. The decay and weight loss rates of the treated samples were significantly lower than those of the control group, and the respiratory intensity of the fruit was delayed in the experimental group.
Conclusions
In this study, we constructed a recombinant Pichia pastoris strain, which is a promising candidate for extending the shelf life of fruits and has potential applications in the development of new preservatives.
Graphical Abstract
... Although the removal of antibiotics, antibiotic-resistance genes in water pollution is a very important practice (Syranidou and Kalogerakis 2022), it is the fundamental solution for preventing the abuse of antibiotics at the source such as in the fields. In agriculture, study on alternatives to antibiotics has received extensive attention (Kim and Lillehoj 2019; Mwangi et al. 2019). ...
The co-expression of multiple antimicrobial peptides (AMPs) in genetically modified (GM) crops can give plants a broader antibacterial spectrum and lower the pathogen risk of drug resistance. Therefore, four penaeidins (shrimp-derived AMPs) were fused and encoded in an artificial gene (PEN1234), driven by the seed-specific promoter Pzein, with the aim of co-expression in seeds of transgenic rice. The resistant rice plants, acquired via Agrobacterium-mediated transformation and glufosinate screening, were identified by PCR and the modified disk-diffusion method, and eight GM lines with high AMP content in the seeds were obtained. Among them, the PenOs017 line had the largest penaeidin content, at approximately 251–300 μg/g in seeds and 15–47 μg/g in roots and leaves. The AMPs in the seeds kept their antibacterial properties even after the seed had been boiled in hot water and could significantly inhibit the growth of methicillin-resistant Staphylococcus aureus, and AMPs in the leaves could effectively inhibit Xanthomonas oryzae pv. Oryzae. The results indicate that PenOs017 seeds containing AMPs are an ideal raw-material candidate for antibiotic-free food and feed, and may require fewer petrochemical fungicides or bactericides for disease control during cultivation than conventional rice.
... However, pharmaceutical companies are stepping out of investments to develop new antibiotics owing to low profits. Under such circumstances, AMPs are a promising candidate for next-generation antibiotics owing to their rapid and efficient elimination of pathogens (Mwangi et al., 2019). Therefore, it is crucial to identify novel AMPs and elucidate their function as well as the mechanism of action. ...
As the emergence and prevalence of antibiotic-resistant strains have resulted in a global crisis, there is an urgent need for new antimicrobial agents. Antimicrobial peptides (AMPs) exhibit inhibitory activity against a wide spectrum of pathogens and can be utilized as an alternative to conventional antibiotics. In this study, two novel AMPs were identified from the venom transcriptome of the spider Argiope bruennichi (Scopoli, 1772) using in silico methods, and their antimicrobial activity was experimentally validated. Aranetoxin-Ab2a (AATX-Ab2a) and Aranetoxin-Ab3a (AATX-Ab3a) were identified by homology analysis and were predicted to have high levels of antimicrobial activity based on in silico analysis. Both peptides were found to have antibacterial effect against Gram-positive and -negative strains, and, in particular, showed significant inhibitory activity against multidrug-resistant Pseudomonas aeruginosa isolates. In addition, AATX-Ab2a and AATX-Ab3a inhibited animal and vegetable fungal strains, while showing low toxicity to normal human cells. The antimicrobial activity of the peptides was attributed to the increased permeability of microbial membranes. The study described the discovery of novel antibiotic candidates, AATX-Ab2a and AATX-Ab3a, using the spider venom gland transcriptome, and validated an in silico -based method for identifying functional substances from biological resources.
... The mechanism of action of AMPs has been a focus of research for many years, since a better understanding of the way these molecules act could allow for the optimization of their function by modifying their primary, secondary, and tertiary structure [70,79,90,91]. AMPs can be categorized based on their mechanism of action into those that kill by acting on the membrane causing disruption and those that act by non-membrane-disruptive mechanisms. ...
... This allows AMPs to interact with cell membranes, even though it also adds to their hemolytic activity, as AMPs that are highly hydrophobic penetrate erythrocytic membranes to a higher extent [88,89]. The mechanism of action of AMPs has been a focus of research for many years, since a better understanding of the way these molecules act could allow for the optimization of their function by modifying their primary, secondary, and tertiary structure [70,79,90,91]. AMPs can be categorized based on their mechanism of action into those that kill by acting on the membrane causing disruption and those that act by non-membrane-disruptive mechanisms. ...
... AMPs cross the membrane after achieving a particular threshold concentration and perturb bacterial membrane permeability through pore opening. More specifically, AMPs that act by membrane-disrupting mechanisms do so by forming a toroidal pore or a barrel-stave, or via a carpet-like mechanism, with all these causing membrane disruption that leads to the leak of intracellular contents, thus causing cell death ( Figure 1) [70,92]. In all cases, AMPs accumulate and are appropriately organized on the target cell membrane, a process driven by their hydrophobic nature and the electrostatic interaction of their positive net charge with the negatively charged phospholipids on the cell membrane of the target cell [93]. ...
Despite recent medical research and clinical practice developments, the development of antimicrobial resistance (AMR) significantly limits therapeutics for infectious diseases. Thus, novel treatments for infectious diseases, especially in this era of increasing AMR, are urgently needed. There is ongoing research on non-classical therapies for infectious diseases utilizing alternative antimicrobial mechanisms to fight pathogens, such as bacteriophages or antimicrobial peptides (AMPs). AMPs are evolutionarily conserved molecules naturally produced by several organisms, such as plants, insects, marine organisms, and mammals, aiming to protect the host by fighting pathogenic microorganisms. There is ongoing research regarding developing AMPs for clinical use in infectious diseases. Moreover, AMPs have several other non-medical applications in the food industry, such as preservatives, animal husbandry, plant protection, and aquaculture. This review focuses on AMPs, their origins, biology, structure, mechanisms of action, non-medical applications, and clinical applications in infectious diseases.
... Through time, bacterial strains have now developed resistance to numerous antibiotics with the help of overexpression of proteins and genes that can eliminate or modify the antibiotics conferring them to be multidrug-resistant (Mwangi et al., 2019). Multidrug resistance presents a severe problem in the treatment of bacterial infections. ...
... Thus, amphibian skin is considered to harbor a pool of bioactive molecules with great drug potential (Barros et al., 2021;Wang Y. et al., 2021b). At present, bioactive peptides secreted from amphibian skin include antimicrobial peptides, antioxidant peptides, wound healing peptides, bradykinins, anti-infective peptides, hypoglycemic peptides, neurotoxins, and neuroprotective peptides (Xu and Lai, 2015;Shang et al., 2017;Mwangi et al., 2019;Yang et al., 2019;Yin et al., 2019;Yin et al., 2020). Since tylotoin was first identified in salamander skin in 2014, a growing number of amphibian-derived peptides have been shown to promote wound repair . ...
Amphibian-derived wound healing peptides thus offer new intervention measures and strategies for skin wound tissue regeneration. As novel drug lead molecules, wound healing peptides can help analyze new mechanisms and discover new drug targets. Previous studies have identified various novel wound healing peptides and analyzed novel mechanisms in wound healing, especially competing endogenous RNAs (ceRNAs) (e.g., inhibition of miR-663a promotes skin repair). In this paper, we review amphibian-derived wound healing peptides, including the acquisition, identification, and activity of peptides, a combination of peptides with other materials, and the analysis of underlying mechanisms, to better understand the characteristics of wound healing peptides and to provide a molecular template for the development of new wound repair drugs.
... 3 AMPs are typically cationic with fewer than fifty amino acids 4 and classified based on their secondary structure (α-helical, β-sheet, loop, or extended). [5][6][7][8][9][10] AMPs strongly bind to bacterial membranes rich in anionic phospholipids but have lower affinity to mammalian cells which have predominantly zwitterionic headgroups. AMP binding is proposed to cause cell leakage and death 2,5 by altering membrane thickness, promoting phospholipid headgroup clustering, or translocating the membrane to target specific intracellular molecules or processes. ...
Metalation of the N-terminal Amino Terminal Cu(ii)- and Ni(ii)-binding (ATCUN) motif may enhance the antimicrobial properties of piscidins. Molecular dynamics simulations of free and nickelated piscidins 1 and 3 (P1 and P3) were performed in 3 : 1 POPC/POPG and 2.6 : 1 : 0.4 POPC/POPG/aldo-PC bilayers (POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine: POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol; aldo-PC, 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine) bilayer models. Nickel(ii) binding decreases the conformation dynamics of the ATCUN motif and lowers the charge of the N-terminus to allow it to embed deeper in the bilayer without significantly changing the overall depth due to interactions of the charged half-helix of the peptide with the headgroups. Phe1⋯Ni2+ cation-π and Phe2-Phe1 CH-π interactions contribute to a small fraction of structures within the nickelated P1 simulations and may partially protect a bound metal from metal-centered chemical activity. The substitution of Phe2 for Ile2 in P3 sterically blocks conformations with cation-π interactions offering less protection to the metal. This difference between metalated P1 and P3 may indicate a mechanism by which peptide sequence can influence antimicrobial properties. Any loss of bilayer integrity due to chain reversal of the oxidized phospholipid chains of aldo-PC may be enhanced in the presence of metalated piscidins.
... Most hepcidin mature peptides contain eight cysteine residues that form four disulfide bonds (Cys1-Cys8; Cys3-Cys6; Cys2-Cys4; Cys5-Cys7), with highly conserved positions in different organisms [19,59]. Similar to other teleosts, the T. ovatus hepcidin2 mature peptide that contains 22 amino acid residues also has eight cysteine residues, which form disulfide bonds to enhance the structural stability and reduce protein degradation [59,60]. The hairpin β-sheet type structure that is formed with the disulfide bonds then considerably increases their antimicrobial properties in hepcidin [19,61]. ...
Hepcidin, a cysteine-rich antimicrobial peptide, has a highly conserved gene structure in teleosts, and it plays an essential role in host immune response against various pathogenic bacteria. Nonetheless, few studies on the antibacterial mechanism of hepcidin in golden pompano (Trachinotus ovatus) have been reported. In this study, we synthesized a derived peptide, TroHepc2-22, from the mature peptide of T. ovatus hepcidin2. Our results showed that TroHepc2-22 has superior antibacterial abilities against both Gram-negative (Vibrio harveyi and Edwardsiella piscicida) and Gram-positive (Staphylococcus aureus and Streptococcus agalactiae) bacteria. Based on the results of a bacterial membrane depolarization assay and propidium iodide (PI) staining assay in vitro, TroHepc2-22 displayed antimicrobial activity by inducing the bacterial membrane depolarization and changing the bacterial membrane permeability. Scanning electron microscopy (SEM) visualization illustrated that TroHepc2-22 brought about membrane rupturing and the leakage of the cytoplasm for the bacteria. In addition, TroHepc2-22 was verified to have hydrolytic activity on bacterial genomic DNA in view of the results of the gel retardation assay. In terms of the in vivo assay, the bacterial loads of V. harveyi in the tested immune tissues (liver, spleen, and head kidney) were significantly reduced in T. ovatus, revealing that TroHepc2-22 significantly enhanced the resistance against V. harveyi infection. Furthermore, the expressions of immune-related genes, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin 1-β (IL-1β), IL-6, Toll-like receptor 1 (TLR1), and myeloid differentiation factor 88 (MyD88) were significantly increased, indicating that TroHepc2-22 might regulate inflammatory cytokines and activate immune-related signaling pathways. To summarize, TroHepc2-22 possesses appreciable antimicrobial activity and plays a vital role in resisting bacterial infection. The observation of our present study unveils the excellent application prospect of hepcidin as a substitute for antibiotics to resist pathogenic microorganisms in teleosts.
