Exploiting Interkingdom Interactions for Development of Small-Molecule Inhibitors of Candida albicans Biofilm Formation

F Jerry Reen; John P Phelan; Lorna Gallagher; David F Woods; Rachel M Shanahan; Rafael Cano; Eoin Ó Muimhneacháin; Gerard P McGlacken; Fergal O'Gara

doi:10.1128/AAC.00190-16

Exploiting Interkingdom Interactions for Development of Small-Molecule Inhibitors of Candida albicans Biofilm Formation

Antimicrob Agents Chemother. 2016 Sep 23;60(10):5894-905. doi: 10.1128/AAC.00190-16. Print 2016 Oct.

Authors

F Jerry Reen¹, John P Phelan¹, Lorna Gallagher¹, David F Woods¹, Rachel M Shanahan², Rafael Cano², Eoin Ó Muimhneacháin², Gerard P McGlacken², Fergal O'Gara³

Affiliations

¹ Biomerit Research Centre, School of Microbiology, University College Cork-National University of Ireland, Cork, Ireland.
² School of Chemistry and Analytical and Biological Chemistry Research Facility (ABCRF), University College Cork-National University of Ireland, Cork, Ireland.
³ Biomerit Research Centre, School of Microbiology, University College Cork-National University of Ireland, Cork, Ireland School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia f.ogara@ucc.ie.

Abstract

A rapid decline in the development of new antimicrobial therapeutics has coincided with the emergence of new and more aggressive multidrug-resistant pathogens. Pathogens are protected from antibiotic activity by their ability to enter an aggregative biofilm state. Therefore, disrupting this process in pathogens is a key strategy for the development of next-generation antimicrobials. Here, we present a suite of compounds, based on the Pseudomonas aeruginosa 2-heptyl-4(1H)-quinolone (HHQ) core quinolone interkingdom signal structure, that exhibit noncytotoxic antibiofilm activity toward the fungal pathogen Candida albicans In addition to providing new insights into what is a clinically important bacterium-fungus interaction, the capacity to modularize the functionality of the quinolone signals is an important advance in harnessing the therapeutic potential of signaling molecules in general. This provides a platform for the development of potent next-generation small-molecule therapeutics targeting clinically relevant fungal pathogens.

MeSH terms

4-Quinolones / chemistry
4-Quinolones / pharmacology
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Biofilms / drug effects
Candida albicans / drug effects*
Candida albicans / physiology
Cell Line
Fungal Proteins / genetics
Gene Expression Regulation, Fungal / drug effects
Humans
Membrane Glycoproteins / genetics
Pseudomonas aeruginosa / chemistry*
Pseudomonas aeruginosa / drug effects
Pseudomonas aeruginosa / pathogenicity
Quinolones / chemistry
Quinolones / pharmacology
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*

Substances

2-heptyl-3-hydroxy-4-quinolone
2-heptyl-4-quinolone
4-Quinolones
ALS3 protein, Candida albicans
Antifungal Agents
ECE1 protein, Candida albicans
Fungal Proteins
HWP1 protein, Candida albicans
Membrane Glycoproteins
Quinolones
Small Molecule Libraries

Grants and funding

G.P.M. thanks the Irish Research Council (R.M.S. and R.C.) and the UCC Strategic Research Fund (E.O.M.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.