scholarly journals In vivo synthesis of monolysocardiolipin and cardiolipin by Acinetobacter baumannii phospholipase D and effect on cationic antimicrobial peptide resistance

2020 ◽  
Vol 22 (12) ◽  
pp. 5300-5308
Author(s):  
Katharina Pfefferle ◽  
Patrizia Lopalco ◽  
Jennifer Breisch ◽  
Anna Siemund ◽  
Angela Corcelli ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Acinetobacter Baumannii ◽  
Phospholipase D ◽  
Cationic Antimicrobial Peptide ◽  
Antimicrobial Peptide Resistance ◽  
In Vivo Synthesis

scholarly journals A Systematic Study of the Stability, Safety, and Efficacy of the de novo Designed Antimicrobial Peptide PepD2 and Its Modified Derivatives Against Acinetobacter baumannii

2021 ◽  
Vol 12 ◽  
Author(s):  
Sung-Pang Chen ◽  
Eric H-L Chen ◽  
Sheng-Yung Yang ◽  
Pin-Shin Kuo ◽  
Hau-Ming Jan ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Antimicrobial Peptide ◽  
Acinetobacter Baumannii ◽  
De Novo ◽  
Multidrug Resistant ◽  
Hek293 Cells ◽  
Amino Acid Residues ◽  
Bacteria And Fungi ◽  
The Stability

Searching for new antimicrobials is a pressing issue to conquer the emergence of multidrug-resistant (MDR) bacteria and fungi. Antimicrobial peptides (AMPs) usually have antimicrobial mechanisms different from those of traditional antibiotics and bring new hope in the discovery of new antimicrobials. In addition to antimicrobial activity, stability and target selectivity are important concerns to decide whether an antimicrobial peptide can be applied in vivo. Here, we used a simple de novo designed peptide, pepD2, which contains only three kinds of amino acid residues (W, K, L), as an example to evaluate how the residues and modifications affect the antimicrobial activity against Acinetobacter baumannii, stability in plasma, and toxicity to human HEK293 cells. We found that pepI2 with a Leu→Ile substitution can decrease the minimum bactericidal concentrations (MBC) against A. baumannii by one half (4 μg/mL). A D-form peptide, pepdD2, in which the D-enantiomers replaced the L-enantiomers of the Lys(K) and Leu(L) residues, extended the peptide half-life in plasma by more than 12-fold. PepD3 is 3-residue shorter than pepD2. Decreasing peptide length did not affect antimicrobial activity but increased the IC50 to HEK293 cells, thus increased the selectivity index (SI) between A. baumannii and HEK293 cells from 4.7 to 8.5. The chain length increase of the N-terminal acyl group and the Lys→Arg substitution greatly enhanced the hemolytic activity, hence those modifications are not good for clinical application. Unlike colistin, the action mechanism of our peptides relies on negatively charged lipids rather than lipopolysaccharides. Therefore, not only gram-negative bacteria but also gram-positive bacteria can be killed by our peptides.

scholarly journals Manipulating Active Structure and Function of Cationic Antimicrobial Peptide CM15 with the Polysulfonated Drug Suramin: A Step Closer to in Vivo Complexity

ChemBioChem ◽  
2019 ◽  
Vol 20 (12) ◽  
pp. 1578-1590 ◽  
Author(s):  
Mayra Quemé‐Peña ◽  
Tünde Juhász ◽  
Judith Mihály ◽  
Imola Cs. Szigyártó ◽  
Kata Horváti ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Structure And Function ◽  
Cationic Antimicrobial Peptide ◽  
Active Structure ◽  
And Function

scholarly journals Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8

2009 ◽  
Vol 206 (9) ◽  
pp. 1983-1994 ◽  
Author(s):  
Dipyaman Ganguly ◽  
Georgios Chamilos ◽  
Roberto Lande ◽  
Josh Gregorio ◽  
Stephan Meller ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Inflammatory Responses ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Cationic Antimicrobial Peptide ◽  
Tnf Α ◽  
Peptide Complexes ◽  
Human Dendritic Cells ◽  
Dying Cells

Dendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid–recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA–LL37 complexes activate TLR7 and, like self-DNA–LL37 complexes, trigger the secretion of IFN-α without inducing maturation or the production of IL-6 and TNF-α. In contrast to self-DNA–LL37 complexes, self-RNA–LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-α and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA–LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.

scholarly journals Identification of a Genetic Locus Responsible for Antimicrobial Peptide Resistance inClostridium difficile

2010 ◽  
Vol 79 (1) ◽  
pp. 167-176 ◽  
Author(s):  
Shonna M. McBride ◽  
Abraham L. Sonenshein
Keyword(s):  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Abc Transporter ◽  
Genetic Locus ◽  
Polymyxin B ◽  
Transcriptional Analysis ◽  
Cationic Antimicrobial Peptide ◽  
Low Levels ◽  
Antimicrobial Peptide Resistance ◽  
Abc Transporter Genes

ABSTRACTClostridium difficilecauses chronic intestinal disease, yet little is understood about how the bacterium interacts with and survives in the host. To colonize the intestine and cause persistent disease, the bacterium must circumvent killing by host innate immune factors, such as cationic antimicrobial peptides (CAMPs). In this study, we investigated the effect of model CAMPs on growth and found thatC. difficileis not only sensitive to these compounds but also responds to low levels of CAMPs by expressing genes that lead to CAMP resistance. By plating the bacterium on medium containing the CAMP nisin, we isolated a mutant capable of growing in three times the inhibitory concentration of CAMPs. This mutant also showed increased resistance to the CAMPs gallidermin and polymyxin B, demonstrating tolerance to different types of antimicrobial peptides. We identified the mutated gene responsible for the resistance phenotype as CD1352. This gene encodes a putative orphan histidine kinase that lies adjacent to a predicted ABC transporter operon (CD1349 to CD1351). Transcriptional analysis of the ABC transporter genes revealed that this operon was upregulated in the presence of nisin in wild-type cells and was more highly expressed in the CD1352 mutant. The insertional disruption of the CD1349 gene resulted in significant decreases in resistance to the CAMPs nisin and gallidermin but not polymyxin B. Because of their role in cationic antimicrobial peptide resistance, we propose the designationcprABCfor genes CD1349 to CD1351 andcprKfor the CD1352 gene. These results provide the first evidence of aC. difficilegene associated with antimicrobial peptide resistance.

scholarly journals Crystallographic study of the phosphoethanolamine transferase EptC required for polymyxin resistance and motility inCampylobacter jejuni

2014 ◽  
Vol 70 (10) ◽  
pp. 2730-2739 ◽  
Author(s):  
Christopher D. Fage ◽  
Dusty B. Brown ◽  
Joseph M. Boll ◽  
Adrian T. Keatinge-Clay ◽  
M. Stephen Trent
Keyword(s):  
Cell Surface ◽  
Lipid A ◽  
Catalytic Domain ◽  
Transmembrane Domain ◽  
Cationic Antimicrobial Peptide ◽  
Cell Surface Structures ◽  
Zinc Binding Site ◽  
Flagellar Assembly ◽  
Antimicrobial Peptide Resistance

The foodborne enteric pathogenCampylobacter jejunidecorates a variety of its cell-surface structures with phosphoethanolamine (pEtN). Modifying lipid A with pEtN promotes cationic antimicrobial peptide resistance, whereas post-translationally modifying the flagellar rod protein FlgG with pEtN promotes flagellar assembly and motility, which are processes that are important for intestinal colonization. EptC, the pEtN transferase required for all known pEtN cell-surface modifications inC. jejuni, is a predicted inner-membrane metalloenzyme with a five-helix N-terminal transmembrane domain followed by a soluble sulfatase-like catalytic domain in the periplasm. The atomic structure of the catalytic domain of EptC (cEptC) was crystallized and solved to a resolution of 2.40 Å. cEptC adopts the α/β/α fold of the sulfatase protein family and harbors a zinc-binding site. A phosphorylated Thr266 residue was observed that was hypothesized to mimic a covalent pEtN–enzyme intermediate. The requirement for Thr266 as well as the nearby residues Asn308, Ser309, His358 and His440 was ascertainedvia in vivoactivity assays on mutant strains. The results establish a basis for the design of pEtN transferase inhibitors.

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