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Volume 169, Issue 3

Structural modification of the alkylquinoline cell–cell communication signal, HHQ, leads to benzofuranoquinolines with anti-virulence behaviour in ESKAPE pathogens Open Access

This article is part of the Environmental Sensing and Cell-Cell Communication collection

Abstract

Microbial populations have evolved intricate networks of negotiation and communication through which they can coexist in natural and host ecosystems. The nature of these systems can be complex and they are, for the most part, poorly understood at the polymicrobial level. The Pseudomonas Quinolone Signal (PQS) and its precursor 4-hydroxy-2-heptylquinoline (HHQ) are signal molecules produced by the important nosocomial pathogen . They are known to modulate the behaviour of co-colonizing bacterial and fungal pathogens such as , and . While the structural basis for alkyl-quinolone signalling within has been studied extensively, less is known about how structural derivatives of these molecules can influence multicellular behaviour and population-level decision-making in other co-colonizing organisms. In this study, we investigated a suite of small molecules derived initially from the HHQ framework, for anti-virulence activity against ESKAPE pathogens, at the species and strain levels. Somewhat surprisingly, with appropriate substitution, loss of the alkyl chain (present in HHQ and PQS) did not result in a loss of activity, presenting a more easily accessible synthetic framework for investigation. Virulence profiling uncovered significant levels of inter-strain variation among the responses of clinical and environmental isolates to small-molecule challenge. While several lead compounds were identified in this study, further work is needed to appreciate the extent of strain-level tolerance to small-molecule anti-infectives among pathogenic organisms.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): anti-virulence , antimicrobial resistance , biofilm , ESKAPE pathogens , HHQ and Pseudomonas aeruginosa
Funding
This study was supported by the:
  • National Health and Medical Research Council (Award APP1183640 2020-5)
    • Principle Award Recipient: FergalO’Gara
  • Cystic Fibrosis Foundation (Award OGARA1710)
    • Principle Award Recipient: FergalO’Gara
  • Higher Education Authority (Award TL19UCC1481/02)
    • Principle Award Recipient: F.Jerry Reen
  • Science Foundation Ireland (Award SFI/12/IP/1315)
    • Principle Award Recipient: GerardP. McGlacken
  • Health Research Board (Award MRCG-2018-16)
    • Principle Award Recipient: FergalO’Gara
  • Health Research Board (Award HRB-ILP-POR-2019-004)
    • Principle Award Recipient: FergalO’Gara
  • Science Foundation Ireland (Award 12/RC/2275_2)
    • Principle Award Recipient: F.Jerry Reen
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2023-03-02
2024-04-25
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Structural modification of the Pseudomonas aeruginosa alkylquinoline cell–cell communication signal, HHQ, leads to benzofuranoquinolines with anti-virulence behaviour in ESKAPE pathogens
Microbiology 169, 001303 (2023); https://doi.org/10.1099/mic.0.001303
/content/journal/micro/10.1099/mic.0.001303
/content/journal/micro/10.1099/mic.0.001303
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