The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids (N-alkylated glycine oligomers), β-peptoids (N-alkylated β-alanine oligomers), β3-peptides, α/β3-peptides, α-peptide/β-peptoid hybrids, α/γ N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.
Natural products and analogues are a source of antibacterial drug discovery. Considering drug resistance levels emerging for antibiotics, identification of bacterial metalloenzymes and the synthesis of selective inhibitors are interesting for antibacterial agent development. Peptide nucleic acids are attractive antisense and antigene agents representing a novel strategy to target pathogens due to their unique mechanism of action. Antisense inhibition and development of antisense peptide nucleic acids is a new approach to antibacterial agents. Due to the increased resistance of biofilms to antibiotics, alternative therapeutic options are necessary. To develop antimicrobial strategies, optimised in vitro and in vivo models are needed. In vivo models to study biofilm-related respiratory infections, device-related infections: ventilator-associated pneumonia, tissue-related infections: chronic infection models based on alginate or agar beads, methods to battle biofilm-related infections are discussed. Drug delivery in case of antibacterials often is a serious issue therefore this review includes overview of drug delivery nanosystems.
Running title: Barbadin modulates specific neutrophil functions Abbreviations: Aoc = 2-aminooctanoic acid; AF = Alexa Fluor; AP2 = clathrin adaptor protein 2; AUC = area under the curve; BRET = bioluminescence resonance energy transfer; BSA = bovine serum albumin; CL = chemiluminescence; DMEM = Dulbecco's modified Eagle medium; DMSO = dimethyl sulfoxide; DPBS = Dulbecco's phosphate-buffered saline; FPR = formyl peptide receptor; GPCR = G protein-coupled receptor; HBSS = Hank's balanced salt solution; HRP = horseradish peroxidase; Lau = Lauroyl; KRG = Krebs-Ringer phosphate buffer: MOI = multiplicity of infection; MPO = myeloperoxidase; βNPhe = N-phenylmethylβ-alanine; βNrpe = N-(R)-1-phenylethyl-β-alanine; PFA = paraformaldehyde; PKC = protein kinase C; PLC = phospholipase C; PMA = phorbol 12-myristate 13-acetate; RhB = rhodamine B; RT = room temperature; ROS = reactive oxygen species; SOD = superoxide dismutase; TR-FRET = time-resolved förster resonance energy transfer AbstractFormyl peptide receptor 2 (FPR2), a member of the family of G protein-coupled receptors (GPCRs), mediates neutrophil migration, a response that has been linked to -arrestin recruitment. -Arrestin regulates GPCR endocytosis and can also elicit non-canonical receptor signaling. To determine the poorly understood role of β-arrestin in FPR2 endocytosis and in NADPH-oxidase activation in neutrophils, Barbadin was used as a research tool in this study.Barbadin has been shown to bind the clathrin adaptor protein (AP2) and thereby prevent arrestin/AP2 interaction and -arrestin-mediated GPCR endocytosis. In agreement with this, AP2/-arrestin interaction induced by an FPR2-specific agonist was inhibited by Barbadin.Unexpectedly, however, Barbadin did not inhibit FPR2 endocytosis, indicating that a mechanism independent of -arrestin/AP2 interaction may sustain FPR2 endocytosis. This was confirmed by the fact, that FPR2 also underwent agonist-promoted endocytosis in -arrestin deficient cells, albeit at a diminished level as compared to wild type cells. Dissection of the Barbadin effects on FPR2-mediated neutrophil functions including NADPH-oxidase activation mediated release of reactive oxygen species (ROS) and chemotaxis reveled that Barbadin had no effect on chemotactic migration whereas the release of ROS was potentiated/primed. The effect of Barbadin on ROS production was reversible, independent of -arrestin recruitment, and similar to that induced by latrunculin A. Taken together, our data demonstrate that endocytic uptake of FPR2 occurs independently of -arrestin, while Barbadin selectively augments FPR2-mediated neutrophil ROS production independently of receptor endocytosis.Given that Barbadin binds to AP2 and prevents the AP2/-arrestin interaction, our results indicate a role for AP2 in FPR2-mediated ROS release from human neutrophils. a large number of ligands belonging to different chemical classes [5][6][7]. Depending on the agonists examined, the signals generated by FPR2 mediate primarily pro-inflammatoryactivities, yet anti-in...
Aims: This systematic review was carried out to determine whether synthetic peptidomimetics exhibit significant advantages over antimicrobial peptides (AMPs) in terms of in vitro potency. Structural features – molecular weight, charge and length – were examined for correlations with activity. Methods: Original research articles reporting minimum inhibitory concentration (MIC) values against Escherichia coli, indexed until 31 December 2020, were searched in PubMed/ScienceDirect/Google Scholar and evaluated using mixed-effects models. Results: In vitro antimicrobial activity of peptidomimetics resembled that of AMPs. Net charge significantly affected MIC values (p < 0.001) with a trend of 4.6% decrease for increments in charge by +1. Conclusion: AMPs and antibacterial peptidomimetics exhibit similar potencies, providing an opportunity to exploit the advantageous stability and bioavailability typically associated with peptidomimetics.
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