Antimicrobial properties of analgesic kyotorphin peptides unraveled through atomic force microscopy

Ribeiro, Marta M. B.; Franquelim, Henri G.; Torcato, Inês M.; Ramu, Vasanthakumar G.; Heras, Montserrat; Bardajı́, Eduard; Castanho, Miguel A. R. B.

doi:10.1016/j.bbrc.2012.03.065

Cited by 21 publications

(15 citation statements)

References 23 publications

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“…Fosfomycin has the ability to penetrate into the fluid of the interstitial space of soft tissues (Frossard et al 2000) to reach levels sufficient to substantially inhibit the growth of relevant bacteria at the target site. The pharmacokinetic and pharmacodynamic properties of fosfomycin facilitate design of drug doses with clinically relevant concentrations for sites such as lungs, bone, soft tissue, and serum and heart valves (Roussos et al 2009 (Eaton et al 2008), kyotorphin peptide (Ribeiro et al 2012), carvacrol (Storia et al 2011) on Staphylococcal aureus biofilms. The nanoscale visualization and characterization of Staphylococcus aureus cells (Ribeiro et al 2012) demonstrated that kyotorphin perturbed the bacterial cell-wall membrane by blebbing, lysis and disruption.…”

Section: Introductionmentioning

confidence: 99%

“…The pharmacokinetic and pharmacodynamic properties of fosfomycin facilitate design of drug doses with clinically relevant concentrations for sites such as lungs, bone, soft tissue, and serum and heart valves (Roussos et al 2009 (Eaton et al 2008), kyotorphin peptide (Ribeiro et al 2012), carvacrol (Storia et al 2011) on Staphylococcal aureus biofilms. The nanoscale visualization and characterization of Staphylococcus aureus cells (Ribeiro et al 2012) demonstrated that kyotorphin perturbed the bacterial cell-wall membrane by blebbing, lysis and disruption. The molecular mechanism of nanoconjugated vancomycin (Chakraborty et al 2012) towards antimicrobial therapeutic approaches in treating Staphylococcus aureus at the nanoscale proved that AFM is a potential tool in understanding the types of antimicrobial induced bacterial cell-wall damage.…”

Section: Introductionmentioning

confidence: 99%

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Atomic force microscopy study of the antibacterial effect of fosfomycin on methicillin-resistant Staphylococcus pseudintermedius

Neethirajan

DiCicco

2013

Appl Nanosci

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The influence of fosfomycin on methicillinresistant Staphylococcus pseudintermedius (MRSP) as the target cell was studied by atomic force microscopy (AFM). Nanoscale images of the effects of the antibiotic fosfomycin on this gram-positive bacterium's cell were obtained in situ without fixing agents. Our study has demonstrated substantial morphological and topographical differences between the control and fosfomycin-treated MRSP cells. The AFM investigations further revealed the rough surface morphology and a 30 % shrinkage in size of the fosfomycin-treated cell and the leakage of cytoplasmic components from the cell. The damage of cell membrane integrity and the cell surface degradation as observed elaborates the antibacterial activity of fosfomycin. The AFM image analysis also reveals that the fosfomycin inhibits cell division, and prevents the adhesion on the surface discouraging the biofilm attachment. The microtitre plate assay results conform to the atomic force microscopy image analysis. This is the first visual demonstration of the effect of fosfomycin on MRSP cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Atomic force microscopy study of the antibacterial effect of fosfomycin on methicillin-resistant Staphylococcus pseudintermedius

Neethirajan

DiCicco

2013

Appl Nanosci

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“…Furthermore, previous studies showed that KTP derivatives were inactive against Gram-negative bacteria (Ribeiro et al 2012), but the results presented here suggest that these peptides can still act as anti-inflammatory and sepsis molecules (beyond analgesic) to target a variety of inflammatory and pain disorders. Although the KTP derivatives have been shown to bind LPS, further studies will be conducted to elucidate how they block the biological effects of LPS.…”

Section: Discussionmentioning

confidence: 86%

The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: insights of a lipid-mediated mechanism

et al. 2015

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Recently, a designed class of efficient analgesic drugs derived from an endogenous neuropeptide, kyotorphin (KTP, Tyr-Arg) combining C-terminal amidation (KTP-NH2) and N-terminal conjugation to ibuprofen (Ib), IbKTP-NH2, was developed. The Ib moiety is an enhancer of KTP-NH2 analgesic action. In the present study, we have tested the hypothesis that KTP-NH2 is an enhancer of the Ib anti-inflammatory action. Moreover, the impact of the IbKTP-NH2 conjugation on microcirculation was also evaluated by a unified approach based on intravital microscopy in the murine cremasteric muscle. Our data show that KTP-NH2 and conjugates do not cause damage on microcirculatory environment and efficiently decrease the number of leukocyte rolling induced by lipopolysaccharide (LPS). Isothermal titration calorimetry showed that the drugs bind to LPS directly thus contributing to LPS aggregation and subsequent elimination. In a parallel study, molecular dynamics simulations and NMR data showed that the IbKTP-NH2 tandem adopts a preferential "stretched" conformation in lipid bilayers and micelles, with the simulations indicating that the Ib moiety is anchored in the hydrophobic core, which explains the improved partition of IbKTP-NH2 to membranes and the permeability of lipid bilayers to this conjugate relative to KTP-NH2. The ability to bind glycolipids concomitant to the anchoring in the lipid membranes through the Ib residue explains the analgesic potency of IbKTP-NH2 given the enriched glycocalyx of the blood-brain barrier cells. Accumulation of IbKTP-NH2 in the membrane favors both direct permeation and local interaction with putative receptors as the location of the KTP-NH2 residue of IbKTP-NH2 and free KTP-NH2 in lipid membranes is the same.

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“…This shape is known as echinocyte and is reversible. Regardless these changes all derivatives were virtually not toxic to RBCs (Ribeiro et al, 2012). …”

Section: Ktp Derivatives Beyond Analgesiamentioning

confidence: 99%

“…KTP (net charge: +1), KTP-NH 2 (+2), IbKTP-NH 2 (+1) and IbKTP (0) were tested against Gram-negative Escherichia coli ( E. coli ) and Gram-positive Staphylococcus aureus ( S. aureus ). (Ribeiro et al, 2012). All derivatives were inactive against E. coli up to 100 μM but they were active against S. aureus , with the exception of KTP.…”

Section: Ktp Derivatives Beyond Analgesiamentioning

confidence: 99%

Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives

2017

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The endogenous peptide kyotorphin (KTP) has been extensively studied since it was discovered in 1979. The dipeptide is distributed unevenly over the brain but the majority is concentrated in the cerebral cortex. The putative KTP receptor has not been identified yet. As many other neuropeptides, KTP clearance is mediated by extracellular peptidases and peptide transporters. From the wide spectrum of biological activity of KTP, analgesia was by far the most studied. The mechanism of action is still unclear, but researchers agree that KTP induces Met-enkephalins release. More recently, KTP was proposed as biomarker of Alzheimer disease. Despite all that, KTP limited pharmacological value prompted researchers to develop derivatives more lipophilic and therefore more prone to cross the blood–brain barrier (BBB), and also more resistant to enzymatic degradation. Conjugation of KTP with functional molecules, such as ibuprofen, generated a new class of compounds with additional biological properties. Moreover, the safety profile of these derivatives compared to opioids and their efficacy as neuroprotective agents greatly increases their pharmacological value.

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Antimicrobial properties of analgesic kyotorphin peptides unraveled through atomic force microscopy

Cited by 21 publications

References 23 publications

Atomic force microscopy study of the antibacterial effect of fosfomycin on methicillin-resistant Staphylococcus pseudintermedius

Atomic force microscopy study of the antibacterial effect of fosfomycin on methicillin-resistant Staphylococcus pseudintermedius

The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: insights of a lipid-mediated mechanism

Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives

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