1887

Abstract

In recent years, the alkyl-quinolone molecular framework has already provided a rich source of bioactivity for the development of novel anti-infective compounds. Based on the quorum-sensing signalling molecules 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS) from the nosocomial pathogen , modifications have been developed with markedly enhanced anti-biofilm bioactivity towards important fungal and bacterial pathogens, including and . Here we show that antibacterial activity of HHQ against is species-specific and it requires an exquisite level of structural fidelity within the alkyl-quinolone molecular framework. Antibacterial activity was demonstrated against the serious human pathogens and as well as a panel of bioluminescent squid symbiont isolates. In contrast, growth and biofilm formation was unaffected in the presence of HHQ and all the structural variants tested. In general, modification to almost all of the molecule except the alkyl-chain end, led to loss of activity. This suggests that the bacteriostatic activity of HHQ requires the concerted action of the entire framework components. The only exception to this pattern was deuteration of HHQ at the C3 position. HHQ modified with a terminal alkene at the quinolone alkyl chain retained bacteriostatic activity and was also found to activate PqsR signalling comparable to the native agonist. The data from this integrated analysis provides novel insights into the structural flexibility underpinning the signalling activity of the complex alkyl-quinolone molecular communication system.

Funding
This study was supported by the:
  • Irish Research Council (Award SFI/RC/2275)
    • Principle Award Recipient: Gerard P McGlacken
  • Irish Research Council (Award SFI/12/IP/1315)
    • Principle Award Recipient: Gerard P McGlacken
  • Health Research Board (Award MRCG-2014-6)
    • Principle Award Recipient: Fergal O'Gara
  • Irish Research Council (Award GOIPG/2014/647)
    • Principle Award Recipient: Fergal O'Gara
  • Science Foundation Ireland (Award 15/TIDA/2977)
    • Principle Award Recipient: Fergal O'Gara
  • Science Foundation Ireland (Award SSPC-2)
    • Principle Award Recipient: Fergal O'Gara
  • European Commission (Award EU2020-634486-2015)
    • Principle Award Recipient: Fergal O'Gara
  • Health Research Board (Award MRCG-2018-6)
    • Principle Award Recipient: Fergal O'Gara
  • Enterprise Ireland (Award CF-2017-0757-P)
    • Principle Award Recipient: Fergal O'Gara
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2019-12-20
2024-03-29
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