Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

Deslouches, Berthony; Montelaro, Ronald C.; Urish, Ken; Di, Y. Peter

doi:10.3390/pharmaceutics12060501

Cited by 46 publications

(39 citation statements)

References 162 publications

(239 reference statements)

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“…It has been suggested that cationicity and acetylation at N -terminal contribute to improve the activity of AMPs [ 29 ]; Therefore, three positive amino acids and/or acetylation at N -terminal were further introduced on the basis of two nonapeptides. As a consequence, we constructed three novel dodecapeptides including WR-12, WRK-12 and WKK-12 with acetylation at the N -terminus and amidation at the C -terminus.…”

Section: Resultsmentioning

confidence: 99%

Potent Broad-Spectrum Antibacterial Activity of Amphiphilic Peptides against Multidrug-Resistant Bacteria

Shi

Tong

et al. 2020

Microorganisms

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The emergence and prevalence of multidrug-resistant (MDR) bacteria particularly Gram-negative bacteria presents a global crisis for human health. Colistin and tigecycline were recognized as the last resort of defenses against MDR Gram-negative pathogens. However, the emergence and prevalence of MCR or Tet(X)-mediated acquired drug resistance drastically impaired their clinical efficacy. It has been suggested that antimicrobial peptides might act a crucial role in combating antibiotic resistant bacteria owing to their multiple modes of action and characteristics that are not prone to developing drug resistance. Herein, we report a safe and stable tryptophan-rich amphiphilic peptide termed WRK-12 with broad-spectrum antibacterial activity against various MDR bacteria, including MRSA, colistin and tigecycline-resistant Escherichia coli. Mechanistical studies showed that WRK-12 killed resistant E. coli through permeabilizing the bacterial membrane, dissipating membrane potential and triggering the production of reactive oxygen species (ROS). Meanwhile, WRK-12 significantly inhibited the formation of an E. coli biofilm in a dose-dependent manner. These findings revealed that amphiphilic peptide WRK-12 is a promising drug candidate in the fight against MDR bacteria.

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Section: Resultsmentioning

confidence: 99%

Potent Broad-Spectrum Antibacterial Activity of Amphiphilic Peptides against Multidrug-Resistant Bacteria

Shi

Tong

et al. 2020

Microorganisms

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“…Several studies on AMPs reveal a contextual problem—namely, AMPs not behaving the same in vivo as in vitro. In addition to showing a different behaviour with changing pH and ion concentrations, some AMPs can bind to plasma proteins in serum, which renders the AMPs ineffective 49 . We thus propose further investigation of PLNC8 αβ, where in vivo experiments are a priority.…”

Section: Discussionmentioning

confidence: 99%

Plantaricin NC8 αβ prevents Staphylococcus aureus-mediated cytotoxicity and inflammatory responses of human keratinocytes

Musa

Wiman

Selegård

et al. 2021

Sci Rep

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Multidrug resistance bacteria constitue an increasing global health problem and the development of novel therapeutic strategies to face this challenge is urgent. Antimicrobial peptides have been proven as potent agents against pathogenic bacteria shown by promising in vitro results. The aim of this study was to characterize the antimicrobial effects of PLNC8 αβ on cell signaling pathways and inflammatory responses of human keratinocytes infected with S. aureus. PLNC8 αβ did not affect the viability of human keratinocytes but upregulated several cytokines (IL-1β, IL-6, CXCL8), MMPs (MMP1, MMP2, MMP9, MMP10) and growth factors (VEGF and PDGF-AA), which are essential in cell regeneration. S. aureus induced the expression of several inflammatory mediators at the gene and protein level and PLNC8 αβ was able to significantly suppress these effects. Intracellular signaling events involved primarily c-Jun via JNK, c-Fos and NFκB, suggesting their essential role in the initiation of inflammatory responses in human keratinocytes. PLNC8 αβ was shown to modulate early keratinocyte responses, without affecting their viability. The peptides have high selectivity towards S. aureus and were efficient at eliminating the bacteria and counteracting their inflammatory and cytotoxic effects, alone and in combination with low concentrations of gentamicin. We propose that PLNC8 αβ may be developed to combat infections caused by Staphylococcus spp.

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“…Bactericidal effect of the APIM-peptide in planktonic MRSE cultures was already detected after 30 min incubation ( Figure 1A ), while it took 8 h before vancomycin completely killed the planktonic culture ( Figure 1B ). An engineered cationic antimicrobial peptide called WLBU2, now in phase 1 trials for treatment of PJIs ( Deslouches et al, 2020 ), has shown comparable effect as APIM-peptides on staphylococcus with regard to rapid bactericidal effects; S. aureus where killed at 2x MIC already after 10 min ( Mandell et al, 2017 ). We detected re-growth in less than 50% of the time-killing experiments using 1x MIC of APIM-peptide ( Supplementary Figure S1 ); however, this is likely due to slightly different assay conditions than in the MIC-assay.…”

Section: Discussionmentioning

confidence: 99%

Novel Peptides Targeting the β-Clamp Rapidly Kill Planktonic and Biofilm Staphylococcus epidermidis Both in vitro and in vivo

et al. 2021

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Antimicrobial resistance is an increasing threat to global health and challenges the way we treat infections. Peptides containing the PCNA interacting motif APIM (APIM-peptides) were recently shown to bind to the bacterial PCNA homolog, the beta (β)-clamp, and to have both antibacterial and anti-mutagenic activities. In this study we explore the antibacterial effects of these peptides on Staphylococcus epidermidis, a bacterial species commonly found in prosthetic joint infections (PJI). Drug-resistant bacterial isolates from PJIs often lead to difficult-to-treat chronic infections. We show that APIM-peptides have a rapid bactericidal effect which when used at sublethal levels also increase the efficacy of gentamicin. In addition, APIM-peptides reduce development and eliminate already existing S. epidermidis biofilm. To study the potential use of APIM-peptides to prevent PJI, we used an in vivo bone graft model in rats where APIM-peptide, gentamicin, or a combination of the two was added to cement. The bone grafts containing cement with the combination was more effective than cement containing only gentamicin, which is the current standard of care. In summary, these results suggest that APIM-peptides can be a promising new drug candidate for anti-infective implant materials to use in the fight against resistant bacteria and chronic PJI.

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Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

Cited by 46 publications

References 162 publications

Potent Broad-Spectrum Antibacterial Activity of Amphiphilic Peptides against Multidrug-Resistant Bacteria

Potent Broad-Spectrum Antibacterial Activity of Amphiphilic Peptides against Multidrug-Resistant Bacteria

Plantaricin NC8 αβ prevents Staphylococcus aureus-mediated cytotoxicity and inflammatory responses of human keratinocytes

Novel Peptides Targeting the β-Clamp Rapidly Kill Planktonic and Biofilm Staphylococcus epidermidis Both in vitro and in vivo

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