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 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 Changes in the Ultrastructure of Staphylococcus aureus Treated with Cationic Peptides and Chlorhexidine

2020 ◽  
Vol 8 (12) ◽  
pp. 1991
Author(s):  
Alina Grigor’eva ◽  
Alevtina Bardasheva ◽  
Anastasiya Tupitsyna ◽  
Nariman Amirkhanov ◽  
Nina Tikunova ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Membrane ◽  
Antimicrobial Peptides ◽  
Membrane Damage ◽  
Observation Time ◽  
Resistant Bacteria ◽  
Cationic Peptides ◽  
Bacterial Cells ◽  
Cell Membrane Damage

Antimicrobial peptides, including synthetic ones, are becoming increasingly important as a promising tool to fight multidrug-resistant bacteria. We examined the effect of cationic peptides H2N-Arg9-Phe2-C(O)NH2 and H2N-(Lys-Phe-Phe)3-Lys-C(O)NH2 on Staphylococcus aureus, which remains one of the most harmful pathogens. Antiseptic chlorhexidine served as reference preparation. We studied viability of S. aureus and examined its ultrastructure under treatment with 100 µM of R9F2 or (KFF)3K peptides or chlorhexidine using transmission electron microscopy of ultrathin sections. Bacterial cells were sampled as kinetic series starting from 1 min up to 4 h of treatment with preparations. Both peptides caused clearly visible damage of bacteria cell membrane within 1 min. Incubation of S. aureus with R9F2 or (KFF)3K peptides led to cell wall thinning, loss of cytoplasm structure, formation of mesosome-derived multimembrane structures and “decorated fibers” derived from DNA chains. The effect of R9F2 peptides on S. aureus was more severe than the effect of (KFF)3K peptides. Chlorhexidine heavily damaged the bacteria cell wall, in particular in areas of septa formation, while cytoplasm kept its structure within the observation time. Our study showed that cell membrane damage is critical for S. aureus viability; however, we believe that cell wall disorders should also be taken into account when analyzing the effects of the mechanisms of action of antimicrobial peptides (AMPs).

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 Staphylococcal-Produced Bacteriocins and Antimicrobial Peptides: Their Potential as Alternative Treatments for Staphylococcus aureus Infections

Antibiotics ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 40 ◽  
Author(s):  
Logan L. Newstead ◽  
Katarina Varjonen ◽  
Tim Nuttall ◽  
Gavin K. Paterson
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptides ◽  
Genome Mining ◽  
Resistant Bacteria ◽  
Coagulase Negative Staphylococci ◽  
Novel Treatments ◽  
Wide Range ◽  
Almost All

Staphylococcus aureus is an important pathogen of both humans and animals, implicated in a wide range of infections. The emergence of antibiotic resistance has resulted in S. aureus strains that are resistant to almost all available antibiotics, making treatment a clinical challenge. Development of novel antimicrobial approaches is now a priority worldwide. Bacteria produce a range of antimicrobial peptides; the most diverse of these being bacteriocins. Bacteriocins are ribosomally synthesised peptides, displaying potent antimicrobial activity usually against bacteria phylogenetically related to the producer strain. Several bacteriocins have been isolated from commensal coagulase-negative staphylococci, many of which display inhibitory activity against S. aureus in vitro and in vivo. The ability of these bacteriocins to target biofilm formation and their novel mechanisms of action with efficacy against antibiotic-resistant bacteria make them strong candidates as novel therapeutic antimicrobials. The use of genome-mining tools will help to advance identification and classification of bacteriocins. This review discusses the staphylococcal-derived antimicrobial peptides displaying promise as novel treatments for S. aureus infections.

scholarly journals Staphylococcus aureus Virulence Affected by an Alternative Nisin A Resistance Mechanism

2020 ◽  
Vol 86 (8) ◽  
Author(s):  
Miki Kawada-Matsuo ◽  
Atsuko Watanabe ◽  
Kaoru Arii ◽  
Yuichi Oogai ◽  
Kazuyuki Noguchi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Hemolytic Activity ◽  
Resistant Strain ◽  
Antibacterial Agents ◽  
Food Additives ◽  
Resistance Mechanism ◽  
Resistant Bacteria ◽  
Food Preservatives ◽  
Content Type ◽  
Lower Survival Rate

ABSTRACT Nisin A is a bacteriocin produced by Lactococcus lactis and is widely used as a food preservative. Staphylococcus aureus has the BraRS-VraDE system that provides resistance against low concentrations of nisin A. BraRS is a two-component system that induces the expression of the ABC transporter VraDE. Previously, we isolated a highly nisin A-resistant strain with increased VraDE expression due to a mutation in braRS. In this study, we isolated S. aureus MW2 mutants with BraRS-VraDE-independent nisin A resistance. These mutants, designated SAN2 (S. aureus nisin resistant) and SAN469, had a mutation in pmtR, which encodes a transcriptional regulator responsible for the expression of the pmtABCD operon. As a result, these mutants exhibited increased expression of PmtABCD, a transporter responsible for the export of phenol-soluble modulin (PSM). Characterization of the mutants revealed that they have decreased susceptibility to human β-defensin-3 (hBD3) and LL37, which are innate immune factors. Additionally, these mutants showed higher hemolytic activity than the original MW2 strain. Furthermore, in a mouse bacteremia model, the SAN2 strain exhibited a lower survival rate than the original MW2 strain. These results indicate that the increased expression of pmtABCD due to a pmtR mutation is an alternative nisin A resistance mechanism that also affects virulence in S. aureus. IMPORTANCE Recently, the emergence of antibiotic-resistant bacteria has resulted in serious problems for chemotherapy. In addition, many antibacterial agents, such as disinfectants and food additives, are widely used. Therefore, there is a possibility that bacteria are becoming resistant to some antibacterial agents. In this study, we investigated whether Staphylococcus aureus can become resistant to nisin A, one of the bacteriocins applied as a food additive. We isolated a highly nisin A-resistant strain designated SAN2 that displayed increased expression of Pmt proteins, which are involved in the secretion of virulence factors called phenol-soluble modulins (PSMs). This strain also showed decreased susceptibility to human antimicrobial peptides and increased hemolytic activity. In addition, SAN2 showed increased lethal activity in a mouse bacteremia model. Our study provides new insights into the possibility that the acquisition of resistance against food preservatives may modulate virulence in S. aureus, suggesting that we need to pay more attention to the use of food preservatives together with antibiotics.

scholarly journals Haemophilus ducreyi SapA Contributes to Cathelicidin Resistance and Virulence in Humans

2010 ◽  
Vol 78 (3) ◽  
pp. 1176-1184 ◽  
Author(s):  
Kristy L. B. Mount ◽  
Carisa A. Townsend ◽  
Sherri D. Rinker ◽  
Xiaoping Gu ◽  
Kate R. Fortney ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Mutant Strain ◽  
Virulence Factor ◽  
Formation Rate ◽  
Resistance Mechanism ◽  
Bacterial Virulence ◽  
Haemophilus Ducreyi ◽  
Wild Type ◽  
Human Volunteers ◽  
Antimicrobial Peptide Resistance

ABSTRACT Haemophilus ducreyi is an extracellular pathogen of human epithelial surfaces that resists human antimicrobial peptides (APs). The organism's genome contains homologs of genes sensitive to antimicrobial peptides (sap operon) in nontypeable Haemophilus influenzae. In this study, we characterized the sap-containing loci of H. ducreyi 35000HP and demonstrated that sapA is expressed in broth cultures and H. ducreyi-infected tissue; sapA is also conserved among both class I and class II H. ducreyi strains. We constructed a nonpolar sapA mutant of H. ducreyi 35000HP, designated 35000HPsapA, and compared the percent survival of wild-type 35000HP and 35000HPsapA exposed to several human APs, including α-defensins, β-defensins, and the cathelicidin LL-37. Unlike an H. influenzae sapA mutant, strain 35000HPsapA was not more susceptible to defensins than strain 35000HP was. However, we observed a significant decrease in the survival of strain 35000HPsapA after exposure to LL-37, which was complemented by introducing sapA in trans. Thus, the Sap transporter plays a role in resistance of H. ducreyi to LL-37. We next compared mutant strain 35000HPsapA with strain 35000HP for their ability to cause disease in human volunteers. Although both strains caused papules to form at similar rates, the pustule formation rate at sites inoculated with 35000HPsapA was significantly lower than that of sites inoculated with 35000HP (33.3% versus 66.7%; P = 0.007). Together, these data establish that SapA acts as a virulence factor and as one mechanism for H. ducreyi to resist killing by antimicrobial peptides. To our knowledge, this is the first demonstration that an antimicrobial peptide resistance mechanism contributes to bacterial virulence in humans.

scholarly journals MprF-Mediated Lysinylation of Phospholipids in Staphylococcus aureus Leads to Protection against Oxygen-Independent Neutrophil Killing

2003 ◽  
Vol 71 (1) ◽  
pp. 546-549 ◽  
Author(s):  
Sascha A. Kristian ◽  
Manuela Dürr ◽  
Jos A. G. Van Strijp ◽  
Birgid Neumeister ◽  
Andreas Peschel
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptides ◽  
Host Defense ◽  
Membrane Lipids ◽  
Human Monocytes ◽  
Wild Type ◽  
Cationic Antimicrobial Peptides ◽  
The Impact ◽  
Defense Molecules

ABSTRACT Staphylococcus aureus achieves resistance to defensins and similar cationic antimicrobial peptides (CAMPs) by modifying anionic membrane lipids via MprF with l-lysine, which leads to repulsion of these host defense molecules. S. aureus ΔmprF, which lacks the modification, was very efficiently killed by neutrophil defensins and CAMP-producing leukocytes, even when oxygen-dependent killing was disrupted, but was as susceptible as wild-type bacteria to inactivation by myeloperoxidase or human monocytes lacking defensins. These results demonstrate the impact and specificity of MprF-mediated CAMP resistance and underscore the role of defensin-like peptides in innate host defense.

scholarly journals An alternative nisin A resistance mechanism affects virulence in Staphylococcus aureus

2019 ◽  
Author(s):  
Miki Kawada-Matsuo ◽  
Atsuko Watanabe ◽  
Kaoru Arii ◽  
Yuichi Oogai ◽  
Kazuyuki Noguchi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Hemolytic Activity ◽  
Antibacterial Agents ◽  
Food Additives ◽  
Resistance Mechanism ◽  
Resistant Mutant ◽  
Resistant Bacteria ◽  
Original Strain ◽  
Lower Survival Rate ◽  
High Level

AbstractNisin A is a bacteriocin produced by Lactococcus lactis and is widely used as a food preservative. Staphylococcus aureus has the BraRS-VraDE system providing resistance against low concentrations of nisin A. The BraRS is one of a two-component system that senses nisin A by BraS and finally induces the expression of ABC transporter VraDE by phosphorylated BraR. Previously, we isolated a highly nisin A resistant strain with increased VraDE expression due to a mutation of braRS. In this study, we isolated a BraRS-VraDE-independent, nisin A resistant mutant from S. aureus MW2. These mutants, designated SAN2 (S. aureusnisin resistant) and SAN469, had a mutation in pmtR (MW1875) which encodes a transcriptional regulator responsible for the expression of the pmtA-D operon. As a result, this mutant exhibited a high level of constitutive production of PmtA-D, a transporter responsible for the export of phenol soluble modulin (PSM). We also obtained two pmtA-D overexpressing, nisin A resistant mutants which contained a point mutation in pmtR from other S. aureus strains.Characterization of the mutants revealed that they have a decreased susceptibility to human beta defensin-3 and LL37, which are innate immune factors. Additionally, these mutants showed higher hemolytic activity than the MW2 original strain. Furthermore, in a mouse bacteremia model, the SAN2 strain exhibited a lower survival rate than the MW2 original strain. These results indicate that the over expression of pmtA-D due to the pmtR mutation is an alternative nisin A resistance, which also affects virulence in S. aureus.Author SummaryRecently, the emergence of antibiotic resistant bacteria such as MRSA, MDRP and CRE have brought serious problems for chemotherapy in the world. In addition, many antibacterial agents such as disinfectants and food additives are widely used. Therefore, it raises the possibility that bacteria are becoming resistant to all antibacterial agents. In this study, we investigated whether S. aureus become resistant against nisin A, one of the food additives. Finally, we isolated nisin A highly resistant S. aureus strains. Among these strains, we identified that one strain designated as SAN2 showed nisin A resistance by the overproduction of Pmts which were involved in the secretion of virulence factors called PSMs. We identified a mutation of pmtR gene encoding a regulator for pmt genes. SAN2 strain showed the decreased susceptibility to human antimicrobial peptides and the increased hemolytic activity. Finally, SAN2 showed higher lethal activity in mouse bacteremia model. Our study provides new insights into that S. aureus may cause resistance against various antibacterial food additives, together with the altering the virulence.

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