期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1861, 期 4, 页码 848-859出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2017.01.029
关键词
Biofllm; Persisters; Antimicrobial peptides; Kanamycin; ESKAPE; Anti-inflammatory
资金
- Egyptian Cultural and Educational Bureau (ECEB) in Washington DC, USA
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1412902] Funding Source: National Science Foundation
Background: The worldwide emergence of antibiotic resistance represents a serious medical threat. The ability of these resistant pathogens to form biofilms that are highly tolerant to antibiotics further aggravates the situation and leads to recurring infections. Thus, new therapeutic approaches that adopt novel mechanisms of action are urgently needed. To address this significant problem, we conjugated the antibiotic kanamycin with a novel antimicrobial peptide (P14LRR) to develop a kanamycin peptide conjugate (P14KanS). Methods: Antibacterial activities were evaluated in vitro and in vivo using a Caenorhabditis elegans model. Additionally, the mechanism of action, antibiofilm activity and anti-inflammatory effect of PI4KanS were investigated. Results: P14KanS exhibited potent antimicrobial activity against ESKAPE pathogens. P14KanS demonstrated a >= 128-fold improvement in MIC relative to kanamycin against kanamycin-resistant strains. Mechanistic studies confirmed that P14KanS exerts its antibacterial effect by selectively disrupting the bacterial cell membrane. Unlike many antibiotics, PI4KanS demonstrated rapid bactericidal activity against stationary phases of both Grampositive and Gram-negative pathogens. Moreover, P14KanS was superior in disrupting adherent bacterial biofilms and in killing intracellular pathogens as compared to conventional antibiotics. Furthermore, P14KanS demonstrated potent anti-inflammatory activity via the suppression of LPS-induced proinflammatory cytokines. Finally, PJ4KanS protected C. elegans from lethal infections of both Gram-positive and Gram-negative pathogens. Conclusions: The potent in vitro and in vivo activity of PI4KanS warrants further investigation as a potential therapeutic agent for bacterial infections. General significance: This study demonstrates that equipping kanamycin with an antimicrobial peptide is a promising method to tackle bacterial biofilms and address bacterial resistance to aminoglycosides. (C) 2017 Elsevier B.V. All rights reserved.
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