RT Journal Article
SR Electronic
T1 Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.03.01.530582
DO 10.1101/2023.03.01.530582
A1 Christopher Jonkergouw
A1 Ngong Kodiah Beyeh
A1 Ekaterina Osmekhina
A1 Katarzyna Leskinen
A1 S. Maryamdokht Taimoory
A1 Dmitrii Federov
A1 Eduardo Anaya-Plaza
A1 Mauri A. Kostiainen
A1 John F. Trant
A1 Robin H. A. Ras
A1 Päivi Saavalainen
A1 Markus B. Linder
YR 2023
UL http://biorxiv.org/content/early/2023/03/01/2023.03.01.530582.abstract
AB 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 eukatryotic 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.Competing Interest StatementThe authors have declared no competing interest.