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

Christopher Jonkergouw (), Ngong Kodiah Beyeh, Ekaterina Osmekhina, Katarzyna Leskinen, S. Maryamdokht Taimoory, Dmitrii Fedorov, Eduardo Anaya-Plaza, Mauri A. Kostiainen, John F. Trant, Robin H. A. Ras, Päivi Saavalainen () and Markus B. Linder ()
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Christopher Jonkergouw: Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems
Ngong Kodiah Beyeh: Oakland University, Department of Chemistry
Ekaterina Osmekhina: Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems
Katarzyna Leskinen: University of Helsinki, Translational Immunology Research Program
S. Maryamdokht Taimoory: University of Windsor, Department of Chemistry and Biochemistry
Dmitrii Fedorov: Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems
Eduardo Anaya-Plaza: Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems
Mauri A. Kostiainen: Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems
John F. Trant: University of Windsor, Department of Chemistry and Biochemistry
Robin H. A. Ras: Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems
Päivi Saavalainen: University of Helsinki, Translational Immunology Research Program
Markus B. Linder: Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37749-6

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