SAAP-148 and halicin exhibit synergistic antimicrobial activity against antimicrobial-resistant bacteria in skin but not airway epithelial culture models

Article

作者: Dorin, Julia R ; Hiemstra, Pieter S ; Lennard, Patrick R ; Nibbering, Peter H

AbstractBackgroundThe escalating global threat of antimicrobial resistance (AMR) necessitates the development of novel antimicrobial agents, innovative strategies, and representative infection models to combat AMR bacterial infections. Host defence peptides (HDPs) and their derivatives have been proposed as complements to conventional antibiotics due to their antibacterial activity and modulation of the immune response.ObjectivesThis study investigated the novel use of the HDP-derived synthetic antibacterial and anti-biofilm peptide (SAAP)-148 as a pretreatment in epithelial tissue models to prevent colonization by AMR bacteria. The combined activities of SAAP-148 pretreatment with post-infection halicin to treat infections were also explored.MethodsEmploying cultured human skin equivalents (HSEs) and primary bronchial epithelial cells (PBECs) as models of tissue infection, we examined the prophylactic and therapeutic effects of SAAP-148, both singularly and in combination with the repurposed antibiotic halicin, against AMR bacteria. We additionally interrogated the response of HSE and PBEC cultures to SAAP-148 treatment via confocal microscopy and quantitative PCR of native HDPs and inflammatory cytokine genes.ResultsOur findings demonstrated that pretreatment with SAAP-148 significantly reduces colonization of HSEs and PBECs by AMR Staphylococcus aureus and Pseudomonas aeruginosa. Confocal microscopy revealed differential uptake and localization of SAAP-148 in these tissues, correlating with its distinct activity in these tissues. SAAP-148 exposure temporarily increased expression of the HDPs cathelicidin (CAMP) and β-defensin 1 (DEFB1), and the cytokine IL-8 (CXCL8), which did not correlate with the transient antibacterial activity observed. Sequential treatment with SAAP-148 prior to infection with AMR S. aureus and post-infection halicin treatment demonstrated synergistic activity in HSEs, whereas this combined activity was indifferent in PBEC cultures.ConclusionsThese results support SAAP-148 as a candidate for pre-infection prophylaxis and synergistic antibiotic therapy with halicin in skin, broadening the potential of both agents to address AMR bacterial infection.

2025-02-27·Journal of Medicinal Chemistry

Peptide Double-Stapling and Arginine N-Glycosylation Triggered the Development of Therapeutic Antimicrobial Peptides Capable of Killing Drug-Resistant Bacteria in Mice

Article

作者: Xue, Jingwen ; Li, Yulei ; Fu, Yinxue ; Cong, Wei ; Lu, Zhiyuan ; Yan, Fang ; Ding, Yanjiao ; Hu, Honggang ; Song, Nannan ; Li, Xiang

Antimicrobial peptides SAAP-148 exhibited excellent antimicrobial activities but suffered from inherent disadvantages, including cytotoxicity and poor proteolytic stability. Herein, we developed a novel strategy combining one unique silver-catalyzed solid-phase glycosylation-enabled arginine N-glycosylation strategy and all-hydrocarbon peptide double-stapling, and five-round peptide libraries were rationally constructed containing over 50 stapled and/or arginine N-glycosylated peptides. SLP-51 consisting of two introduced all-hydrocarbon staples and the C-terminal arginine glycosylation exhibited superior in vitro antimicrobial activities against drug-resistant Gram-positive or -negative clinical isolates. SLP-51 also exhibited improved proteolytic stability than the parent peptide SLP-0, and importantly, significantly weakened hemolysis. Experimental and modeling mechanism research indicated that SLP-51 exerted similar but stronger killing abilities by destroying the integrality of the bacterial membranes. In both skin wound and drug-resistant bacterial pneumonia models, SLP-51 showcased a potent therapeutic effect in treating both MRSA and Klebsiella pneumoniae infection in vivo and dramatical improvement of inflammatory injury.

2024-04-01·Probiotics and Antimicrobial Proteins

Novel Antimicrobial Peptide SAAP Mutant as a Better Adjuvant to Sulbactam-Based Treatments Against Clinical Strains of XDR Acinetobacter baumannii

Article

作者: Ramaiah, Sudha ; Naha, Aniket

The production of extended spectrum β-lactamases (ESBLs) in extensively drug-resistant (XDR) strains of Acinetobacter baumannii has created havoc amongst clinicians making the treatment procedure challenging. Carbapenem-resistant strains have displayed total ineffectiveness towards newer combinations of β-lactam-β-lactamase inhibitors (βL-βLI) in tertiary healthcare settings. Therefore, the present study was aimed to design potential β-lactamase antimicrobial peptide (AMP) inhibitors against ESBLs produced by the strains. We have constructed an AMP mutant library with higher antimicrobial efficacy (range: ~ 15 to 27%) than their parent peptides. The mutants were thoroughly screened based on different physicochemical and immunogenic properties revealing three peptides, namely SAAP-148, HFIAP-1, myticalin-C6 and their mutants with safe pharmacokinetics profile. Molecular docking highlighted SAAP-148_M15 displaying maximum inhibitory potential with lowest binding energies against NDM1 (- 1148.7 kcal/mol), followed by OXA23 (- 1032.5 kcal/mol) and OXA58 (- 925.3 kcal/mol). The intermolecular interaction profiles displayed SAAP-148_M15 exhibiting hydrogen bonds and van der Waals hydrophobic interactions with the crucial residues of metallo β-lactamase [IPR001279] and penicillin-binding transpeptidase [IPR001460] domains. Coarse-grained clustering and molecular dynamics simulations (MDS) further validated the stable backbone profile and minimal residue-level fluctuations of the protein-peptide complex that were maintained throughout the simulation timeframe. The present study hypothesised that the combination of sulbactam (βL) with SAAP-148_M15 (βLI) holds immense potential in inhibiting the ESBLs alongside restoration of sulbactam activity. The current in silico findings upon further experimental validations can pave path towards designing of successful therapeutic strategy against XDR strains of A. baumannii.

100 项与 SAAP-148 相关的药物交易

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