Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii.

Autor: Jonkergouw C; Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland. chris@jonkergouw.nl., Beyeh NK; Oakland University, Department of Chemistry, 146 Library Drive, Rochester, MI, 48309-4479, USA.; Aalto University, School of Science, Department of Applied Physics, Puumiehenkuja 2, Espoo, Finland., Osmekhina E; Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland., Leskinen K; University of Helsinki, Translational Immunology Research Program, Haartmaninkatu 8, 0014, Helsinki, Finland., Taimoory SM; University of Windsor, Department of Chemistry and Biochemistry, Windsor, ON, N9B 3P4, Canada.; University of Michigan, Department of Chemistry, Ann Arbor, MI, USA., Fedorov D; Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland., Anaya-Plaza E; Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland., Kostiainen MA; Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland., Trant JF; University of Windsor, Department of Chemistry and Biochemistry, Windsor, ON, N9B 3P4, Canada., Ras RHA; Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland.; Aalto University, School of Science, Department of Applied Physics, Puumiehenkuja 2, Espoo, Finland., Saavalainen P; University of Helsinki, Translational Immunology Research Program, Haartmaninkatu 8, 0014, Helsinki, Finland. paivi.saavalainen@helsinki.fi.; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland. paivi.saavalainen@helsinki.fi., Linder MB; Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland. markus.linder@aalto.fi.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 14; Vol. 14 (1), pp. 2141. Date of Electronic Publication: 2023 Apr 14.
DOI: 10.1038/s41467-023-37749-6
Abstrakt: The limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations. The binding of homoserine lactones and lipopolysaccharides also sequesters their direct effects as toxins on eukaryotic membranes, neutralizing key tools that promote bacterial colonization and impede immune defenses, both in vitro and in vivo. Pillar[5]arene evades both existing antibiotic resistance mechanisms, as well as the build-up of rapid tolerance/resistance. The versatility of macrocyclic host-guest chemistry provides ample strategies for tailored targeting of virulence in a wide range of Gram-negative infectious diseases.
(© 2023. The Author(s).)
Databáze: MEDLINE
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