scholarly journals Review: Lessons Learned From Clinical Trials Using Antimicrobial Peptides (AMPs)

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabrielle S. Dijksteel ◽  
Magda M. W. Ulrich ◽  
Esther Middelkoop ◽  
Bouke K. H. L. Boekema
Keyword(s):  
Clinical Trials ◽  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Inflammatory Responses ◽  
Membrane Surface ◽  
Lessons Learned ◽  
Resistant Bacteria ◽  
Clinical Implementation ◽  
Host Defense Peptides ◽  
Yeast Fungi

Antimicrobial peptides (AMPs) or host defense peptides protect the host against various pathogens such as yeast, fungi, viruses and bacteria. AMPs also display immunomodulatory properties ranging from the modulation of inflammatory responses to the promotion of wound healing. More interestingly, AMPs cause cell disruption through non-specific interactions with the membrane surface of pathogens. This is most likely responsible for the low or limited emergence of bacterial resistance against many AMPs. Despite the increasing number of antibiotic-resistant bacteria and the potency of novel AMPs to combat such pathogens, only a few AMPs are in clinical use. Therefore, the current review describes (i) the potential of AMPs as alternatives to antibiotics, (ii) the challenges toward clinical implementation of AMPs and (iii) strategies to improve the success rate of AMPs in clinical trials, emphasizing the lessons we could learn from these trials.

scholarly journals Staphylococcus aureus Resistance to Human Defensins and Evasion of Neutrophil Killing via the Novel Virulence Factor Mprf Is Based on Modification of Membrane Lipids with l-Lysine

2001 ◽  
Vol 193 (9) ◽  
pp. 1067-1076 ◽  
Author(s):  
Andreas Peschel ◽  
Ralph W. Jack ◽  
Michael Otto ◽  
L. Vincent Collins ◽  
Petra Staubitz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptides ◽  
Virulence Factor ◽  
Membrane Lipids ◽  
Membrane Surface ◽  
Resistance Mechanism ◽  
Bacterial Pathogen ◽  
Human Neutrophils ◽  
Resistant Bacteria ◽  
Host Defense Peptides

Defensins, antimicrobial peptides of the innate immune system, protect human mucosal epithelia and skin against microbial infections and are produced in large amounts by neutrophils. The bacterial pathogen Staphylococcus aureus is insensitive to defensins by virtue of an unknown resistance mechanism. We describe a novel staphylococcal gene, mprF, which determines resistance to several host defense peptides such as defensins and protegrins. An mprF mutant strain was killed considerably faster by human neutrophils and exhibited attenuated virulence in mice, indicating a key role for defensin resistance in the pathogenicity of S. aureus. Analysis of membrane lipids demonstrated that the mprF mutant no longer modifies phosphatidylglycerol with l-lysine. As this unusual modification leads to a reduced negative charge of the membrane surface, MprF-mediated peptide resistance is most likely based on repulsion of the cationic peptides. Accordingly, inactivation of mprF led to increased binding of antimicrobial peptides by the bacteria. MprF has no similarity with genes of known function, but related genes were identified in the genomes of several pathogens including Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Enterococcus faecalis. MprF thus constitutes a novel virulence factor, which may be of general relevance for bacterial pathogens and represents a new target for attacking multidrug resistant bacteria.

scholarly journals The Lactococcal dgkB (yecE) and dxsA Genes for Lipid Metabolism Are Involved in the Resistance to Cell Envelope-Acting Antimicrobials

2021 ◽  
Vol 22 (3) ◽  
pp. 1014
Author(s):  
Aleksandra Tymoszewska ◽  
Tamara Aleksandrzak-Piekarczyk
Keyword(s):  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Cytoplasmic Membrane ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Membrane Targeting ◽  
Nucleotide Polymorphisms ◽  
Next Generation ◽  
Lipid Ii

The emergence of antibiotic-resistant bacteria led to an urgent need for next-generation antimicrobial agents with novel mechanisms of action. The use of positively charged antimicrobial peptides that target cytoplasmic membrane is an especially promising strategy since essential functions and the conserved structure of the membrane hinder the development of bacterial resistance. Aureocin A53- and enterocin L50-like bacteriocins are highly cationic, membrane-targeting antimicrobial peptides that have potential as next-generation antibiotics. However, the mechanisms of resistance to these bacteriocins and cross-resistance against antibiotics must be examined before application to ensure their safe use. Here, in the model bacterium Lactococcus lactis, we studied the development of resistance to selected aureocin A53- and enterocin L50-like bacteriocins and its correlation with antibiotics. First, to generate spontaneous resistant mutants, L.lactis was exposed to bacteriocin BHT-B. Sequencing of their genomes revealed single nucleotide polymorphisms (SNPs) in the dgkB (yecE) and dxsA genes encoding diacylglycerol kinase and 1-deoxy-D-xylulose 5-phosphate synthase, respectively. Then, selected mutants underwent susceptibility tests with a wide array of bacteriocins and antibiotics. The highest alterations in the sensitivity of studied mutants were seen in the presence of cytoplasmic membrane targeting bacteriocins (K411, Ent7, EntL50, WelM, SalC, nisin) and antibiotics (daptomycin and gramicidin) as well as lipid II cycle-blocking bacteriocins (nisin and Lcn972) and antibiotics (bacitracin). Interestingly, decreased via the SNPs accumulation sensitivity to membrane-active bacteriocins and antibiotics resulted in the concurrently increased vulnerability to bacitracin, carbenicillin, or chlortetracycline. It is suspected that SNPs may result in alterations to the efficiency of the nascent enzymes rather than a total loss of their function as neither deletion nor overexpression of dxsA restored the phenotype observed in spontaneous mutants.

scholarly journals Antimicrobial Peptides: Mechanisms of Action and Resistance

2016 ◽  
Vol 96 (3) ◽  
pp. 254-260 ◽  
Author(s):  
B. Bechinger ◽  
S.-U. Gorr
Keyword(s):  
Cell Wall ◽  
Cell Membrane ◽  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Rare Event ◽  
Mechanisms Of Action ◽  
Current Evidence ◽  
Aggregation State ◽  
Host Defense Peptides ◽  
Bacterial Membranes

More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide’s structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.

scholarly journals Antimicrobial and Antibiofilm Peptides

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 652 ◽  
Author(s):  
Angela Di Somma ◽  
Antonio Moretta ◽  
Carolina Canè ◽  
Arianna Cirillo ◽  
Angela Duilio
Keyword(s):  
Antimicrobial Peptides ◽  
Biofilm Formation ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Antibiofilm Activity ◽  
Chronic Infections ◽  
Planktonic Bacteria ◽  
Hostile Environments

The increasing onset of multidrug-resistant bacteria has propelled microbiology research towards antimicrobial peptides as new possible antibiotics from natural sources. Antimicrobial peptides are short peptides endowed with a broad range of activity against both Gram-positive and Gram-negative bacteria and are less prone to trigger resistance. Besides their activity against planktonic bacteria, many antimicrobial peptides also show antibiofilm activity. Biofilms are ubiquitous in nature, having the ability to adhere to virtually any surface, either biotic or abiotic, including medical devices, causing chronic infections that are difficult to eradicate. The biofilm matrix protects bacteria from hostile environments, thus contributing to the bacterial resistance to antimicrobial agents. Biofilms are very difficult to treat, with options restricted to the use of large doses of antibiotics or the removal of the infected device. Antimicrobial peptides could represent good candidates to develop new antibiofilm drugs as they can act at different stages of biofilm formation, on disparate molecular targets and with various mechanisms of action. These include inhibition of biofilm formation and adhesion, downregulation of quorum sensing factors, and disruption of the pre-formed biofilm. This review focuses on the proprieties of antimicrobial and antibiofilm peptides, with a particular emphasis on their mechanism of action, reporting several examples of peptides that over time have been shown to have activity against biofilm.

scholarly journals Dual functional β-peptide polymer-modified resin beads for bacterial killing and endotoxin adsorption

BMC Materials ◽  
2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Yuxin Qian ◽  
Yue Shen ◽  
Shuai Deng ◽  
Tingyan Liu ◽  
Fan Qi ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Resistant Bacteria ◽  
High Concentration ◽  
Major Step ◽  
Bacterial Killing ◽  
Host Defense Peptides ◽  
Dual Functional ◽  
Resin Beads ◽  
Bacteria Killing

Abstract Background Bacterial infections and endotoxin contaminations are serious problems in the production/manufacture of food, water, drinks, and injections. The development of effective materials to kill bacteria and adsorb endotoxins, particularly those caused by gram-negative bacteria, represents a major step toward improved safety. As synthetic mimic of host defense peptides, β-peptide polymers are not susceptible to bacterial resistance and exhibit potent bacteria-killing abilities upon antibiotic-resistant bacteria. This study investigated the potential of synthetic β-peptide polymer-modified polyacrylate (PA) beads to kill bacteria and remove endotoxin, i.e. lipopolysaccharide (LPS), produced by these bacteria. Results Synthetic β-peptide polymer-modified PA beads displayed strong antimicrobial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus, as well as excellent biocompatibility. In addition, these β-peptide polymer-modified beads removed around 90% of the endotoxins, even at 200 EU/mL of LPS, a very high concentration of LPS. Conclusions β-peptide polymer-modified PA beads are efficient in bacterial killing and endotoxin adsorption. Hence, these modified beads demonstrate the potential application in the production/manufacture of food, water, drinks, and injections.

Antimicrobial peptides: an overview of a promising class of therapeutics

2007 ◽  
Vol 2 (1) ◽  
pp. 1-33 ◽  
Author(s):  
Andrea Giuliani ◽  
Giovanna Pirri ◽  
Silvia Nicoletto
Keyword(s):  
Antimicrobial Peptides ◽  
Multidrug Resistant ◽  
Innate Immune ◽  
Resistant Bacteria ◽  
Yeast Fungi ◽  
Wide Range ◽  
New Development ◽  
Catheter Site ◽  
Conventional Antibiotics

AbstractAntibiotic resistance is increasing at a rate that far exceeds the pace of new development of drugs. Antimicrobial peptides, both synthetic and from natural sources, have raised interest as pathogens become resistant against conventional antibiotics. Indeed, one of the major strengths of this class of molecules is their ability to kill multidrug-resistant bacteria. Antimicrobial peptides are relatively small (6 to 100 aminoacids), amphipathic molecules of variable length, sequence and structure with activity against a wide range of microorganisms including bacteria, protozoa, yeast, fungi, viruses and even tumor cells. They usually act through relatively non-specific mechanisms resulting in membranolytic activity but they can also stimulate the innate immune response. Several peptides have already entered pre-clinical and clinical trials for the treatment of catheter site infections, cystic fibrosis, acne, wound healing and patients undergoing stem cell transplantation. We review the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization.

scholarly journals SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans

2008 ◽  
Vol 7 (8) ◽  
pp. 1318-1327 ◽  
Author(s):  
Kimberly D. Gank ◽  
Michael R. Yeaman ◽  
Satoshi Kojima ◽  
Nannette Y. Yount ◽  
Hyunsook Park ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Host Defense ◽  
Genomic Library ◽  
Inflammatory Responses ◽  
Host Defense Peptides ◽  
Antimicrobial Peptide Resistance ◽  
Null Mutants

ABSTRACT Candida albicans is usually a harmless human commensal. Because inflammatory responses are not normally induced by colonization, antimicrobial peptides are likely integral to first-line host defense against invasive candidiasis. Thus, C. albicans must have mechanisms to tolerate or circumvent molecular effectors of innate immunity and thereby colonize human tissues. Prior studies demonstrated that an antimicrobial peptide-resistant strain of C. albicans, 36082R, is hypervirulent in animal models versus its susceptible counterpart (36082S). The current study aimed to identify a genetic basis for antimicrobial peptide resistance in C. albicans. Screening of a C. albicans genomic library identified SSD1 as capable of conferring peptide resistance to a susceptible surrogate, Saccharomyces cerevisiae. Sequencing confirmed that the predicted translation products of 36082S and 36082R SSD1 genes were identical. However, Northern analyses corroborated that SSD1 is expressed at higher levels in 36082R than in 36082S. In isogenic backgrounds, ssd1Δ/ssd1Δ null mutants were significantly more susceptible to antimicrobial peptides than parental strains but had equivalent susceptibilities to nonpeptide stressors. Moreover, SSD1 complementation of ssd1Δ/ssd1Δ mutants restored parental antimicrobial peptide resistance phenotypes, and overexpression of SSD1 conferred enhanced peptide resistance. Consistent with these in vitro findings, ssd1 null mutants were significantly less virulent in a murine model of disseminated candidiasis than were their parental or complemented strains. Collectively, these results indicate that SSD1 is integral to C. albicans resistance to host defense peptides, a phenotype that appears to enhance the virulence of this organism in vivo.

Antimicrobial Peptides: Amphibian Host Defense Peptides

2019 ◽  
Vol 26 (32) ◽  
pp. 5924-5946 ◽  
Author(s):  
Jiri Patocka ◽  
Eugenie Nepovimova ◽  
Blanka Klimova ◽  
Qinghua Wu ◽  
Kamil Kuca
Keyword(s):  
Antimicrobial Peptides ◽  
Frog Skin ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Amino Acid Residues ◽  
Host Defense Peptides ◽  
Microbial Invasion ◽  
Close Relationship ◽  
Lysine Residues ◽  
Induce Resistance

Antimicrobial Peptides (AMPs) are one of the most common components of the innate immune system that protect multicellular organisms against microbial invasion. The vast majority of AMPs are isolated from the frog skin. Anuran (frogs and toads) skin contains abundant AMPs that can be developed therapeutically. Such peptides are a unique but diverse group of molecules. In general, more than 50% of the amino acid residues form the hydrophobic part of the molecule. Normally, there are no conserved structural motifs responsible for activity, although the vast majority of the AMPs are cationic due to the presence of multiple lysine residues; this cationicity has a close relationship with antibacterial activity. Notably, recent evidence suggests that synthesis of AMPs in frog skin may confer an advantage on a particular species, although they are not essential for survival. Frog skin AMPs exert potent activity against antibiotic-resistant bacteria, protozoa, yeasts, and fungi by permeating and destroying the plasma membrane and inactivating intracellular targets. Importantly, since they do not bind to a specific receptor, AMPs are less likely to induce resistance mechanisms. Currently, the best known amphibian AMPs are esculentins, brevinins, ranacyclins, ranatuerins, nigrocin-2, magainins, dermaseptins, bombinins, temporins, and japonicins-1 and -2, and palustrin-2. This review focuses on these frog skin AMPs and the mechanisms underlying their antimicrobial activity. We hope that this review will provide further information that will facilitate further study of AMPs and cast new light on novel and safer microbicides.

scholarly journals Cathelicidin Antimicrobial Peptides with Reduced Activation of Toll-Like Receptor Signaling Have Potent Bactericidal Activity against Colistin-Resistant Bacteria

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Cheng Kao ◽  
Xiaoyan Lin ◽  
Guanghui Yi ◽  
Yunliang Zhang ◽  
Dean A. Rowe-Magnus ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Bactericidal Activity ◽  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Human Cells ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Human Red Blood Cells ◽  
Minor Injuries

ABSTRACT The world is at the precipice of a postantibiotic era in which medical procedures and minor injuries can result in bacterial infections that are no longer effectively treated by antibiotics. Cathelicidins are peptides produced by animals to combat bacterial infections and to regulate innate immune responses. However, cathelicidins are potent activators of the inflammatory response. Cathelicidins with reduced proinflammatory activity and potent bactericidal activity in the low micromolar range against Gram-negative bacteria have been identified. Motifs in cathelicidins that impact bactericidal activity and cytotoxicity to human cells have been elucidated and used to generate peptides that have reduced activation of proinflammatory cytokine production and reduced cytotoxicity to human cells. The resultant peptides have bactericidal activities comparable to that of colistin and can kill colistin-resistant bacteria. IMPORTANCE Cathelicidins are antimicrobial peptides that can also increase inflammatory responses. This combination of activities can cause complications in the treatment of bacterial infections despite the pressing need for new antimicrobials. We have identified cathelicidins with decreased activation of inflammatory responses. The peptides kill Gram-negative bacteria at low micromolar concentrations by binding to and perturbing the integrity of the bacterial membrane. The peptides were also engineered to further decrease lysis of human red blood cells. The peptides have activities comparable to those of the polymyxins, a class of antibiotics to which plasmid-borne resistance is rapidly spreading and can kill colistin-resistant bacteria. These peptides are promising candidates for the development of novel antibacterial agents.

scholarly journals Antimicrobial Peptides in Farm Animals: An Updated Review on Its Diversity, Function, Modes of Action and Therapeutic Prospects

2020 ◽  
Vol 7 (4) ◽  
pp. 206
Author(s):  
Rohit Kumar ◽  
Syed Azmal Ali ◽  
Sumit Kumar Singh ◽  
Vanya Bhushan ◽  
Manya Mathur ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Wide Spectrum ◽  
Farm Animals ◽  
Resistant Bacteria ◽  
Clinical Implementation ◽  
Antibiotic Resistant ◽  
Systematic Classification ◽  
New Antibiotics ◽  
Host Defense System ◽  
Prospective Application

Antimicrobial peptides (AMPs) are the arsenals of the innate host defense system, exhibiting evolutionarily conserved characteristics that are present in practically all forms of life. Recent years have witnessed the emergence of antibiotic-resistant bacteria compounded with a slow discovery rate for new antibiotics that have necessitated scientific efforts to search for alternatives to antibiotics. Research on the identification of AMPs has generated very encouraging evidence that they curb infectious pathologies and are also useful as novel biologics to function as immunotherapeutic agents. Being innate, they exhibit the least cytotoxicity to the host and exerts a wide spectrum of biological activity including low resistance among microbes and increased wound healing actions. Notably, in veterinary science, the constant practice of massive doses of antibiotics with inappropriate withdrawal programs led to a high risk of livestock-associated antimicrobial resistance. Therefore, the world faces tremendous pressure for designing and devising strategies to mitigate the use of antibiotics in animals and keep it safe for posterity. In this review, we illustrate the diversity of farm animal-specific AMPs, and their biochemical foundations, mode of action, and prospective application in clinics. Subsequently, we present the data for their systematic classification under the major and minor groups, antipathogenic action, and allied bioactivities in the host. Finally, we address the limitations of their clinical implementation and envision areas for further advancement.

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