Azole Resistance of Aspergillus fumigatus Biofilms Is Partly Associated with Efflux Pump Activity

Rajendran, Ranjith; Mowat, Eilidh; McCulloch, Elaine; Lappin, David F.; Jones, Brian; Lang, Sue; Majithiya, Jayesh B.; Warn, Peter; Williams, Craig; Ramage, Gordon

doi:10.1128/aac.01189-10

Cited by 133 publications

(122 citation statements)

References 38 publications

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“…Reduced susceptibility to drugs in BF conditions (60) could also result from an increased activity of efflux pumps and transporter proteins (57). To test this hypothesis, we examined the expression patterns of the 274 genes encoding the major facilitator superfamily (MFS) proteins and the 45 genes encoding the ATPbinding cassette (ABC) proteins (58).…”

Section: Resultsmentioning

confidence: 99%

“…In the lung parenchyma, like in the aerial colony on an agar plate (BF), the A. fumigatus mycelium is covered by an ECM (3,8,35,46,48,57). We reasoned that better understanding the genome-wide transcriptional configuration during BF would provide insight into the genes involved in this process and potentially a better understanding of the establishment of a colony during in vivo growth.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, an ECM is produced when the fungus is grown in aerial static conditions (3). Importantly, in this aerially grown biofilm (BF)-like state, the fungus exhibits reduced susceptibility to antifungal drugs (44,45,57,60) and undergoes major metabolic changes that are thought to be involved in virulence (8,35).…”

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confidence: 99%

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Global Transcriptome Changes Underlying Colony Growth in the Opportunistic Human Pathogen Aspergillus fumigatus

et al. 2012

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Aspergillus fumigatus is the most common and deadly pulmonary fungal infection worldwide. In the lung, the fungus usually forms a dense colony of filaments embedded in a polymeric extracellular matrix. To identify candidate genes involved in this biofilm (BF) growth, we used RNA-Seq to compare the transcriptomes of BF and liquid plankton (PL) growth. Sequencing and mapping of tens of millions sequence reads against the A. fumigatus transcriptome identified 3,728 differentially regulated genes in the two conditions. Although many of these genes, including the ones coding for transcription factors, stress response, the ribosome, and the translation machinery, likely reflect the different growth demands in the two conditions, our experiment also identified hundreds of candidate genes for the observed differences in morphology and pathobiology between BF and PL. We found an overrepresentation of upregulated genes in transport, secondary metabolism, and cell wall and surface functions. Furthermore, upregulated genes showed significant spatial structure across the A. fumigatus genome; they were more likely to occur in subtelomeric regions and colocalized in 27 genomic neighborhoods, many of which overlapped with known or candidate secondary metabolism gene clusters. We also identified 1,164 genes that were downregulated. This gene set was not spatially structured across the genome and was overrepresented in genes participating in primary metabolic functions, including carbon and amino acid metabolism. These results add valuable insight into the genetics of biofilm formation in A. fumigatus and other filamentous fungi and identify many relevant, in the context of biofilm biology, candidate genes for downstream functional experiments.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Global Transcriptome Changes Underlying Colony Growth in the Opportunistic Human Pathogen Aspergillus fumigatus

et al. 2012

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“…The Pel polysaccharide enhances resistance to several antibiotics including aminoglycosides and colistin (22,24,25). Because biofilm formation by A. fumigatus is associated with increased resistance to a number of antifungal agents (26)(27)(28), we hypothesized that GAG may have an analogous function to Pel in enhancing resistance to antifungal agents. To test this hypothesis, we investigated whether Sph3 h or PelA h could potentiate the activity of commonly used antifungal drugs.…”

Section: Sph3 H and Pela H Potentiate Antifungals By Enhancing Theirmentioning

confidence: 99%

Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

Snarr

Baker

Bamford

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

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Galactosaminogalactan and Pel are cationic heteropolysaccharides produced by the opportunistic pathogens Aspergillus fumigatus and Pseudomonas aeruginosa, respectively. These exopolysaccharides both contain 1,4-linked N-acetyl-D-galactosamine and play an important role in biofilm formation by these organisms. Proteins containing glycoside hydrolase domains have recently been identified within the biosynthetic pathway of each exopolysaccharide. Recombinant hydrolase domains from these proteins (Sph3 h from A. fumigatus and PelA h from P. aeruginosa) were found to degrade their respective polysaccharides in vitro. We therefore hypothesized that these glycoside hydrolases could exhibit antibiofilm activity and, further, given the chemical similarity between galactosaminogalactan and Pel, that they might display cross-species activity. Treatment of A. fumigatus with Sph3 h disrupted A. fumigatus biofilms with an EC 50 of 0.4 nM. PelA h treatment also disrupted preformed A. fumigatus biofilms with EC 50 values similar to those obtained for Sph3 h . In contrast, Sph3 h was unable to disrupt P. aeruginosa Pel-based biofilms, despite being able to bind to the exopolysaccharide. Treatment of A. fumigatus hyphae with either Sph3 h or PelA h significantly enhanced the activity of the antifungals posaconazole, amphotericin B, and caspofungin, likely through increasing antifungal penetration of hyphae. Both enzymes were noncytotoxic and protected A549 pulmonary epithelial cells from A. fumigatus-induced cell damage for up to 24 h. Intratracheal administration of Sph3 h was well tolerated and reduced pulmonary fungal burden in a neutropenic mouse model of invasive aspergillosis. These findings suggest that glycoside hydrolases can exhibit activity against diverse microorganisms and may be useful as therapeutic agents by degrading biofilms and attenuating virulence.biofilm | Aspergillus | Pseudomonas | therapeutics | exopolysaccharide

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“…Gordon Ramage presented an in vitro model to monitor adaptive antifungal resistance mechanisms. A. fumigatus biofilms exhibit a phase-dependent resistance against antifungal agents (44), and transcriptional analysis revealed a higher expression of drug efflux pumps in more developed biofilms (45). Furthermore, eDNA, which is released in a phase-dependent manner, not only is important for the biofilm architecture but also contributes to resistance (46).…”

Section: New Insights Into Chronic Biofilm Diseasesmentioning

confidence: 99%

Biofilms 2012: New Discoveries and Significant Wrinkles in a Dynamic Field

Häußler

Fuqua

2013

J Bacteriol

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The ASM 6th Conference on Biofilms was held in Miami, Florida, 29 September to 4 October, 2012. The conference provided an opportunity for the exchange of new findings and ideas with regard to biofilm research. A wide range of findings, spanning applied biology, evolution, ecology, physiology, and molecular biology, were presented at the conference. This review summarizes the presentations with regard to emerging biofilm-related themes.T he ASM 6th Conference on Biofilms was held in Miami, Florida, 29 September to 4 October 2012, and was attended by 447 participants. Of these conferees, 180 were international. The meeting covered an exciting range of topics across the breadth of biofilm research and comprised three keynote lectures and 14 thematically organized sessions. The meeting included two extensive poster sessions for an overall 269 posters, where investigators presented their latest research. Of these posters, 8 distinguished young researchers were recognized at the conference banquet with awards in memory of international leaders in the field of biofilm research: The Bill Characklis Poster Award for Excellence in Engineering in Biofilm Research, the Terry Beveridge Poster Award for Excellence in Biofilm Microscopy, the Peter Gilbert Poster Award for Excellence in Innovation and Biofilm Control, and the Bill Costerton Poster Award for Outstanding Interdisciplinary Biofilm Research. In this review, we summarize the Biofilms 2012 presentations in the individual sessions on emerging biofilm-related themes, including the three keynote talks and several selected posters. We intend for this to provide the attendees of the Biofilms 2012 conference with a synopsis of the scientific highlights presented and to update those who were unable to attend.Biofilms are the products of microbial multicellular interactions, and they adopt physical structures that reflect the summation of complex interactions among their individual constituents. Biofilms form at many different surfaces, including air-solid, airliquid, and liquid-liquid interfaces, and range from single species to highly complex, multispecies assemblies. More and more laboratories have investigated the genetic and physiological bases of biofilm formation and structure for a wide range of bacteria. Various bacterial activities, including cell growth and cell death, nutrient acquisition, waste product accumulation, secretion, motility mechanisms, and exopolysaccharide synthesis, can influence the structure and emergent attributes of biofilms. BIOFILMS, COLONIES, AND WRINKLESNot surprisingly, many of the same properties that are key to biofilms also impact the morphology of simple colonies on solid medium. Although it has long been debated in the biofilm community whether a bacterial colony should be considered a specialized type of biofilm, it is unquestionable that colony morphologies can effectively reflect some of the important attributes of biofilms. At the Biofilms 2012 conference, it was striking how prominently the analysis of bacterial colonies feature...

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Azole Resistance of Aspergillus fumigatus Biofilms Is Partly Associated with Efflux Pump Activity

Cited by 133 publications

References 38 publications

Global Transcriptome Changes Underlying Colony Growth in the Opportunistic Human Pathogen Aspergillus fumigatus

Global Transcriptome Changes Underlying Colony Growth in the Opportunistic Human Pathogen Aspergillus fumigatus

Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

Biofilms 2012: New Discoveries and Significant Wrinkles in a Dynamic Field

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