Dataset Information

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.

SUBMITTER: Reen FJ

PROVIDER: S-EPMC5177741 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Harnessing Bacterial Signals for Suppression of Biofilm Formation in the Nosocomial Fungal Pathogen <i>Aspergillus fumigatus</i>.

Reen F Jerry FJ Phelan John P JP Woods David F DF Shanahan Rachel R Cano Rafael R Clarke Sarah S McGlacken Gerard P GP O'Gara Fergal F

Frontiers in microbiology 20161222

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 ...[more]

PMID: 28066389

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Project description:Aspergillus fumigatus is a potentially deadly opportunistic fungal pathogen. Molecular studies have shaped our understanding of the genes, proteins, and molecules that contribute to A. fumigatus pathogenicity, but few studies have characterized genome-wide patterns of genetic variation at the population level. Of A. fumigatus genomic studies to-date, most focus mainly on single nucleotide polymorphisms and large structural variants, while overlooking the contribution of copy number variation (CNV). CNV is a class of small structural variation defined as loci that vary in their number of copies between individuals due to duplication, gain, or deletion. CNV can influence phenotype, including fungal virulence. In the present study, we characterized the population genomic patterns of CNV in a diverse collection of 71 A. fumigatus isolates using publicly available sequencing data. We used genome-wide single nucleotide polymorphisms to infer the population structure of these isolates and identified three populations consisting of at least 8 isolates. We then computationally predicted genome-wide CNV profiles for each isolate and conducted analyses at the species-, population-, and individual levels. Our results suggest that CNV contributes to genetic variation in A. fumigatus, with ~10% of the genome being CN variable. Our analysis indicates that CNV is non-randomly distributed across the A. fumigatus genome, and is overrepresented in subtelomeric regions. Analysis of gene ontology categories in genes that overlapped CN variants revealed an enrichment of genes related to transposable element and secondary metabolism functions. We further identified 72 loci containing 33 genes that showed divergent copy number profiles between the three A. fumigatus populations. Many of these genes encode proteins that interact with the cell surface or are involved in pathogenicity. Our results suggest that CNV is an important source of genetic variation that could account for some of the phenotypic differences between A. fumigatus populations and isolates.

Project description:Host-associated microbial biofilms can provide protection against pathogen establishment. In many host-microbe symbioses (including, but not limited to humans, plants, insects, and amphibians), there is a correlation between host-associated microbial diversity and pathogen infection risk. Diversity may prevent infection by pathogens through sampling effects and niche complementarity, but an alternative hypothesis may be that microbial biomass is confounded with diversity and that host-associated biofilms are deterring pathogen establishment through space preemption. In this study, we use the amphibian system as a model for host-microbe-pathogen interactions to ask two questions: (i) is bacterial richness confounded with biofilm thickness or cell density, and (ii) to what extent do biofilm thickness, cell density, and bacterial richness each deter the establishment of the amphibian fungal pathogen Batrachochytrium dendrobatidis? To answer these questions, we built a custom biofilm microcosm that mimics the host-environment interface by allowing nutrients to diffuse out of a fine-pore biofilm scaffolding. This created a competitive environment in which bacteria and the fungal pathogen compete for colonization space. We then challenged bacterial biofilms ranging in community richness, biofilm thickness, bacterial cell density, and B. dendrobatidis (also known as Bd)-inhibitory metabolite production with live B. dendrobatidis zoospores to determine how B. dendrobatidis establishment success on membranes varies. We found that biofilm thickness and B. dendrobatidis-inhibitory isolate richness work in complement to reduce B. dendrobatidis establishment success. This work underscores that physical aspects of biofilm communities can play a large role in pathogen inhibition, and in many studies, these traits are not studied. IMPORTANCE Our finding highlights the fact that diversity, as measured through 16S rRNA gene sequencing, may obscure the true mechanisms behind microbe-mediated pathogen defense and that physical space occupation by biofilm-forming symbionts may significantly contribute to pathogen protection. These findings have implications across a wide range of host-microbe systems since 16S rRNA gene sequencing is a standard tool used across many microbial systems. Further, our results are potentially relevant to many host-pathogen systems since host-associated bacterial biofilms are ubiquitous.

Dataset Information

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

Publications

Harnessing Bacterial Signals for Suppression of Biofilm Formation in the Nosocomial Fungal Pathogen <i>Aspergillus fumigatus</i>.

Similar Datasets

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