Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy

Bertelsen, Kresten; Dorosz, Jerzy; Hansen, Sara K.; Nielsen, Niels Chr.; Vosegaard, Thomas

doi:10.1371/journal.pone.0047745

Cited by 42 publications

(34 citation statements)

References 64 publications

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“…It has been shown that compounds that target the cell wall or cell membrane were found to potentiate the activities of other antibiotics (11,18,27,28). Previous work on artificial membranes showed that low concentrations of novicidin result in transient pore formation and increased concentrations cause cell membrane disruption (13,29). It has also been suggested that novicidin accumulates on the membrane surface until a detergent-like disintegration occurs (known as the carpet mechanism) (13).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro

Soren

Brinch

Patel

et al. 2015

Antimicrob Agents Chemother

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cThe spread of antibiotic resistance among Gram-negative bacteria is a serious clinical threat, and infections with these organisms are a leading cause of mortality worldwide. Traditional novel drug development inevitably leads to the emergence of new resistant strains, rendering the new drugs ineffective. Therefore, reviving the therapeutic potentials of existing antibiotics represents an attractive novel strategy. Novicidin, a novel cationic antimicrobial peptide, is effective against Gram-negative bacteria. Here, we investigated novicidin as a possible antibiotic enhancer. The actions of novicidin in combination with rifampin, ceftriaxone, or ceftazidime were investigated against 94 antibiotic-resistant clinical Gram-negative isolates and 7 strains expressing New Delhi metallo-␤-lactamase-1. Using the checkerboard method, novicidin combined with rifampin showed synergy with >70% of the strains, reducing the MICs significantly. The combination of novicidin with ceftriaxone or ceftazidime was synergistic against 89.7% of the ceftriaxone-resistant strains and 94.1% of the ceftazidime-resistant strains. Synergistic interactions were confirmed using time-kill studies with multiple strains. Furthermore, novicidin increased the postantibiotic effect when combined with rifampin or ceftriaxone. Membrane depolarization assays revealed that novicidin alters the cytoplasmic membrane potential of Gram-negative bacteria. In vitro toxicology tests showed novicidin to have low hemolytic activity and no detrimental effect on cell cultures. We demonstrated that novicidin strongly rejuvenates the therapeutic potencies of ceftriaxone or ceftazidime against resistant Gram-negative bacteria in vitro. In addition, novicidin boosted the activity of rifampin. This strategy can have major clinical implications in our fight against antibiotic-resistant bacterial infections.

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Section: Discussionmentioning

confidence: 99%

Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro

Soren

Brinch

Patel

et al. 2015

Antimicrob Agents Chemother

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“…This imbalance causes the peptides to tilt with respect to the bilayer normal and to recruit lipid headgroups to the interior of the membrane to form what is termed a ''toroidal pore''. The resulting lipid distortion is evident from 31 P chemical shifts of oriented samples in ssNMR (14). Melittin is the most studied example of a toroidal pore (6,15,16).…”

Section: Introductionmentioning

confidence: 99%

Simulations of Membrane-Disrupting Peptides II: AMP Piscidin 1 Favors Surface Defects over Pores

Perrin

Cotten

et al. 2016

Biophysical Journal

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Antimicrobial peptides (AMPs) that disrupt bacterial membranes are promising therapeutics against the growing number of antibiotic-resistant bacteria. The mechanism of membrane disruption by the AMP piscidin 1 was examined with multimicrosecond all-atom molecular dynamics simulations and solid-state NMR spectroscopy. The primary simulation was initialized with 20 peptides in four barrel-stave pores in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol bilayer. The four pores relaxed to toroidal by 200 ns, only one porelike structure containing two transmembrane helices remained at 26 ms, and none of the 18 peptides released to the surface reinserted to form pores. The simulation was repeated at 413 K with an applied electric field and all peptides were surface-bound by 200 ns. Trajectories of surface-bound piscidin with and without applied fields at 313 and 413 K and totaling 6 ms show transient distortions of the bilayer/water interface (consistent with 31 P NMR), but no insertion to transmembrane or pore states.15 N chemical shifts confirm a fully surface-bound conformation. Taken together, the simulation and experimental results imply that transient defects rather than stable pores are responsible for membrane disruption by piscidin 1, and likely other AMPs.

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“…Three different models for peptidemembrane interaction are commonly used: barrel-stave, toroidal and carpet models [9][10][11]. It was suggested that collective behaviour of peptides can play a role in the bacterial membrane destruction [12][13][14][15][16][17][18][19]. For instance, using 31 P oriented solid-state NMR experiments it was found that at high peptide concentration alamethicin adopts a transmembrane conformation while the novicidin forms a toroidal pore in the membrane [16].…”

Section: Introductionmentioning

confidence: 99%

“…It was suggested that collective behaviour of peptides can play a role in the bacterial membrane destruction [12][13][14][15][16][17][18][19]. For instance, using 31 P oriented solid-state NMR experiments it was found that at high peptide concentration alamethicin adopts a transmembrane conformation while the novicidin forms a toroidal pore in the membrane [16]. Using solid-state 19 F NMR it was shown that at low concentration the amphiphilic [KIGAKI] 3 peptide binds to membrane as flexible β-strand, without forming any intra or intermolecular Hbonds [13].…”

Section: Introductionmentioning

confidence: 99%

The cooperative behaviour of antimicrobial peptides in model membranes

Wang

Mura

Zhou

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A systematic analysis of the hypothesis of the antimicrobial peptides' (AMPs) cooperative action is performed by means of full atomistic molecular dynamics simulations accompanied by circular dichroism experiments. Several AMPs from the aurein family (2.5,2.6, 3.1), have a similar sequence in the first ten amino acids, are investigated in different environments including aqueous solution, trifluoroethanol (TFE), palmitoyloleoylphosphatidylethanolamine (POPE), and palmitoyloleoylphosphatidylglycerol (POPG) lipid bilayers. It is found that the cooperative effect is stronger in aqueous solution and weaker in TFE. Moreover, in the presence of membranes, the cooperative effect plays an important role in the peptide/lipid bilayer interaction. The action of AMPs is a competition of the hydrophobic interactions between the side chains of the peptides and the hydrophobic region of lipid molecules, as well as the intra peptide interaction. The aureins 2.5-COOH and 2.6-COOH form a hydrophobic aggregate to minimize the interaction between the hydrophobic group and the water. Once that the peptides reach the water/lipid interface the hydrophobic aggregate becomes smaller and the peptides start to penetrate into the membrane. In contrast, aurein 3.1-COOH forms only a transient aggregate which disintegrates once the peptides reached the membrane, and it shows no cooperativity in membrane penetration.

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Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy

Cited by 42 publications

References 64 publications

Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro

Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro

Simulations of Membrane-Disrupting Peptides II: AMP Piscidin 1 Favors Surface Defects over Pores

The cooperative behaviour of antimicrobial peptides in model membranes

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