Harnessing Bacterial Signals for Suppression of Biofilm Formation in the Nosocomial Fungal Pathogen Aspergillus fumigatus

Abstract

Faced with the continued emergence of antibiotic resistance to all known classes of antibiotics, a paradigm shift in approaches toward antifungal therapeutics is required. Well characterized in a broad spectrum of bacterial and fungal pathogens, biofilms are a key factor in limiting the effectiveness of conventional antibiotics. Therefore, therapeutics such as small molecules that prevent or disrupt biofilm formation would render pathogens susceptible to clearance by existing drugs. This is the first report describing the effect of the Pseudomonas aeruginosa alkylhydroxyquinolone interkingdom signal molecules 2-heptyl-3-hydroxy-4-quinolone and 2-heptyl-4-quinolone on biofilm formation in the important fungal pathogen Aspergillus fumigatus. Decoration of the anthranilate ring on the quinolone framework resulted in significant changes in the capacity of these chemical messages to suppress biofilm formation. Addition of methoxy or methyl groups at the C5–C7 positions led to retention of anti-biofilm activity, in some cases dependent on the alkyl chain length at position C2. In contrast, halogenation at either the C3 or C6 positions led to loss of activity, with one notable exception. Microscopic staining provided key insights into the structural impact of the parent and modified molecules, identifying lead compounds for further development.

Novel intermicrobial molecular interaction: Pseudomonas aeruginosa Quinolone Signal (PQS) modulates Aspergillus fumigatus response to iron

“…Relevant to inter-kingdom interactions, fungi may inhibit PQS production, PQS can modulate biofilm formation by yeasts, and is fungistatic against Cryptococcus , though it appears not to influence the morphology or morphological switching in Candida albicans [14, 33, 53]. In a recent study of alkylhydroxyquinolones, including PQS, using our published methodology, PQS was reported to suppress Af biofilm formation, studied at a single high 100 µM concentration [54]. Our observations on biofilm formation here are consistent with that, although our dose-response studies, and of the effect of Fe, and observations on preformed biofilm, illuminate a larger picture with respect to PQS.…”

Synthesis of Benzofuroquinolines via Phosphine‐Free Direct Arylation of 4‐Phenoxyquinolines in Air

“…Following on from our continuing investigation of quinolone and quinoline analogues of HHQ and PQS, using molecules which are “blocked” at the C‐3 position, we chose to apply our intramolecular arylation methodology to a HHQ/PQS analogue (Figure ). Substitution of C‐3 is often crucial as it prevents hydroxylation of HHQ at this position by PqsH.…”

Coinfection with Pseudomonas aeruginosa and Aspergillus fumigatus in cystic fibrosis

“…These induce A. fumigatus production of an extracellular matrix that inhibits A. fumigatus growth by altering cell wall architecture [87]. P. aeruginosa also secrete the interkingdom signalling molecules alkylhydroxyquinolones [88], produced in response to increasing density of bacterial cells, which influence gene expression, phenazine secretion [80] and have been shown to disrupt A. fumigatus biofilm integrity [88].…”