LL-37-derived short antimicrobial peptide KR-12-a5 and its d-amino acid substituted analogs with cell selectivity, anti-biofilm activity, synergistic effect with conventional antibiotics, and anti-inflammatory activity

Kim, Eun Young; Rajasekaran, Ganesan; Shin, Song Yub

doi:10.1016/j.ejmech.2017.05.028

Cited by 92 publications

(80 citation statements)

References 61 publications

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“…The original peptide LL-37 and its fragments have shown their action against preformed biofilms of P. aeruginosa (Overhage et al 2008;Nagant et al 2012) and Acinetobacter baumannii (Feng et al 2013) and in preventing biofilm formation by C. albicans, S. aureus and E. coli (Luo et al 2017). A recent study showed the potential of KR-12-a5 and its analogs in inhibiting multidrug-resistant Pseudomonas aeruginosa biofilm formation, in concentrations much lower than LL-37 (Kim et al 2017). In the present study, KR-12-a5 was less efficient than CHX in reducing S. mutans biofilms by CLSM.…”

Section: Discussionmentioning

confidence: 99%

KR-12-a5 is a non-cytotoxic agent with potent antimicrobial effects against oral pathogens

et al. 2017

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This study evaluated the cytotoxicity and antimicrobial activity of analogs of cationic peptides against microorganisms associated with endodontic infections. L-929 fibroblasts were exposed to LL-37, KR-12-a5 and hBD-3-1C and chlorhexidine (CHX, control), and cell metabolism was evaluated with MTT. The minimal inhibitory concentration (MIC) and the minimal bactericidal/fungicidal concentration (MBC/MFC) of the peptides and CHX were determined against oral pathogens associated with endodontic infections. Enterococcus faecalis and Streptococcus mutans biofilms were cultivated in bovine dentin blocks, exposed to different concentrations of the most efficient antimicrobial peptide and analyzed by confocal laser scanning microscopy. CHX and peptides affected the metabolism of L-929 at concentrations > 31.25 and 500 μg ml, respectively. Among the peptides, KR-12-a5 inhibited growth of both the microorganisms tested with the lowest MIC/MBC/MFC values. In addition, KR-12-a5 significantly reduced E. faecalis and S. mutans biofilms inside dentin tubules. In conclusion, KR-12-a5 is a non-cytotoxic agent with potent antimicrobial and anti-biofilm activity against oral pathogens associated with endodontic infections.

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Section: Discussionmentioning

confidence: 99%

KR-12-a5 is a non-cytotoxic agent with potent antimicrobial effects against oral pathogens

et al. 2017

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“…Synergistic enhancement of antimicrobial activities has been described (McCafferty et al 1999;Acar 2000) and includes mixtures of peptides with conventional antibiotics (Chou et al 2016;Bolosov et al 2017;Kim et al 2017;Payne et al 2017;Rank et al 2017;Sakoulas et al 2017) or different peptides such as dermaseptins, bacteriocins (Mor et al 1994;McCafferty et al 1999), magainin 2 and PGLa (Vaz Gomes et al 1993), or magainin and the cyclic β-sheet tachyplesin I sequence (Kobayashi et al 2001). Here we will shortly summarize findings made with magainin 2 and PGLa which have recently been reviewed in more detail (Marquette and Bechinger 2018).…”

Section: Synergistic Enhancement Of the Activities Of Antimicrobial Pmentioning

confidence: 95%

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

Aisenbrey¹,

Marquette²,

Bechinger³

2019

Advances in Experimental Medicine and Biology

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Even 30 years after the discovery of magainins, biophysical and structural investigations on how these peptides interact with membranes can still bear surprises and add new interesting detail to how these peptides exert their antimicrobial action. Early on, using oriented solid-state NMR spectroscopy, it was found that the amphipathic helices formed by magainins are active when being oriented parallel to the membrane surface. More recent investigations indicate that this in-planar alignment is also found when PGLa and magainin in combination exert synergistic pore-forming activities, where studies on the mechanism of synergistic interaction are ongoing. In a related manner, the investigation of dimeric antimicrobial peptide sequences has become an interesting topic of research which bears promise to refine our views how antimicrobial action occurs. The molecular shape concept has been introduced to explain the effects of lipids and peptides on membrane morphology, locally and globally, and in particular of cationic amphipathic helices that partition into the membrane interface. This concept has been extended in this review to include more recent ideas on soft membranes that can adapt to external stimuli including membrane-disruptive molecules. In this manner, the lipids can change their shape in the presence of low peptide concentrations, thereby maintaining the bilayer properties. At higher peptide concentrations, phase transitions occur which lead to the formation of pores and membrane lytic processes. In the context of the molecular shape concept, the properties of lipopeptides, including surfactins, are shortly presented, and comparisons with the hydrophobic alamethicin sequence are made. Keywords (separated by "-") Magainin-PGLa-Cecropin-LL37-Surfacting alamethicin-Membrane topology-Membrane pore-Membrane macroscopic phase-SMART model-Carpet model-Toroidal pore-Peptide-lipid interactions-Molecular shape concept

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“…The secondary structures of Pep05 and its derivatives were investigated using a Chirascan qCD Spectrometer (Applied Photophysics, United Kingdom). The peptides were dissolved to a final concentration of 0.1 mg/mL in four different solvents, namely, 10 mM phosphate buffer (PB; pH 7.4), 50% TFE/PB, 25 mM SDS in PB, and 0.1% LPS in PB (Kim et al, 2017). Circular dichroism (CD) spectra were recorded from 260 to 190 nm at 25 • C as the average of three scans.…”

Section: Circular Dichroism Spectroscopymentioning

confidence: 99%

D- and Unnatural Amino Acid Substituted Antimicrobial Peptides With Improved Proteolytic Resistance and Their Proteolytic Degradation Characteristics

Xia

et al. 2020

Front. Microbiol.

135

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The transition of antimicrobial peptides (AMPs) from the laboratory to market has been severely hindered by their instability toward proteases in biological systems. In the present study, we synthesized derivatives of the cationic AMP Pep05 (KRLFKKLLKYLRKF) by substituting L -amino acid residues with D - and unnatural amino acids, such as D- lysine, D- arginine, L- 2,4-diaminobutanoic acid (Dab), L- 2,3-diaminopropionic acid (Dap), L- homoarginine, 4-aminobutanoic acid (Aib), and L- thienylalanine, and evaluated their antimicrobial activities, toxicities, and stabilities toward trypsin, plasma proteases, and secreted bacterial proteases. In addition to measuring changes in the concentration of the intact peptides, LC-MS was used to identify the degradation products of the modified AMPs in the presence of trypsin and plasma proteases to determine degradation pathways and examine whether the amino acid substitutions afforded improved proteolytic resistance. The results revealed that both D- and unnatural amino acids enhanced the stabilities of the peptides toward proteases. The derivative DP06, in which all of the L- lysine and L- arginine residues were replaced by D -amino acids, displayed remarkable stability and mild toxicity in vitro but only slight activity and severe toxicity in vivo , indicating a significant difference between the in vivo and in vitro results. Unexpectedly, we found that the incorporation of a single Aib residue at the N-terminus of compound UP09 afforded remarkably enhanced plasma stability and improved activity in vivo . Hence, this derivative may represent a candidate AMP for further optimization, providing a new strategy for the design of novel AMPs with improved bioavailability.

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LL-37-derived short antimicrobial peptide KR-12-a5 and its d-amino acid substituted analogs with cell selectivity, anti-biofilm activity, synergistic effect with conventional antibiotics, and anti-inflammatory activity

Cited by 92 publications

References 61 publications

KR-12-a5 is a non-cytotoxic agent with potent antimicrobial effects against oral pathogens

KR-12-a5 is a non-cytotoxic agent with potent antimicrobial effects against oral pathogens

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

D- and Unnatural Amino Acid Substituted Antimicrobial Peptides With Improved Proteolytic Resistance and Their Proteolytic Degradation Characteristics

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