AUG 21, 2013 10:00 AM PDT

Azole resistance in Aspergillus fumigatus - clinical isolate screening, culture selection, and genetics

C.E. Credits: CE
Speaker

Abstract

In the United States, invasive aspergillosis (IA), an invasive fungal infection of the upper respiratory tract of immune compromised patients, is usually caused by Aspergilus fumigatus, while Aspergillus flavus represents only a small fraction of IA cases. In some countries A. flavus is the most frequent IA pathogen. Recently, we described a novel, highly virulent, aggressively invasive, and drug resistant IA pathogen, Aspergillus tanneri. In mouse models of IA and in a non-vertebrate insect model we observed distinct virulence profiles for the three Aspergillus species. Comparative genomics showed that A. tanneri had a larger genome than the other Aspergilli, encoding nearly 1900 more genes than A. fumigatus. A. tanneri genes had numerous orthologs in the other two genomes, however an abundance of genes are unique to A. tanneri. Among the unique genes were multiple gene clusters that encode biosynthetic genes for the synthesis of secondary metabolites, suggesting that A. tanneri produces novel secondary metabolites that may play a role in its high level of pathogenicity. Analysis of genes commonly associated with drug resistance showed that A. tanneri carried CYP51A mutations resulting in or contributing to azole resistance. An important issue featured in the A. tanneri fatal cases and in clinical management of IA is the general limitation in treatment options - only four classes of drugs are available in the context of ever-increasing drug resistance. Drugs used to treat fungal infections target only two differences between human and fungal cells: the presence of ergosterol in fungal cell membranes and of glucans in their cell walls. There remains an urgent need to understand the broad range of genes encoded in the genomes of fungal pathogens that participate in the resistance to the clinically therapeutic antifungals employed in treating infections. To identify novel mechanisms that mediate azole resistance in A. fumigatus, we used whole genome sequencing of in vitro selected azole-resistant strains. To further refine the most significant mechanisms required for resistance, we developed a genetic-sexual system that enables the analysis of complex traits in A. fumigatus and revealed that at least 6 mechanisms for azole resistance exist in this organism. These include mutations in the target protein, CYP51A, and in an additional co-target HMG CoA reductase. The results from this study identify novel drug targets in A. fumigatus and also show that next-generation sequencing coupled with classical genetics experiments is a powerful way to identify genes involved in complex traits.


Show Resources
You May Also Like
SEP 14, 2021 7:00 AM PDT
C.E. CREDITS
SEP 14, 2021 7:00 AM PDT
Date: September 14, 2021 Time: 7am PDT, 10am EDT, 4pm CEST A conventional thermal cycler has long been a commodity product in the lab and end-point PCR techniques can be completed almost wit...
SEP 17, 2021 12:00 PM CST
C.E. CREDITS
SEP 17, 2021 12:00 PM CST
Date: September 16, 2021 Time: 9:00pm (PDT), 12:00am (EDT) 3D cellular models like organoids and spheroids offer an opportunity to better understand complex biology in a physiologically rele...
MAY 11, 2021 10:00 AM PDT
C.E. CREDITS
MAY 11, 2021 10:00 AM PDT
Date: May 11, 2021 Time: 10:00zm PDT Your samples are some of the most valuable assets in the laboratory. After spending countless hours on extraction and preparation, your conclusions could...
APR 01, 2021 8:00 AM PDT
C.E. CREDITS
APR 01, 2021 8:00 AM PDT
Date: April 01, 2021 Time: 8:00am (PST), 11:00am (EST) Generating therapeutic antibodies is far more challenging than obtaining antibodies that merely recognize their targets. Engineering po...
JUN 09, 2021 7:00 AM PDT
C.E. CREDITS
JUN 09, 2021 7:00 AM PDT
Date: June 9, 2021 Time: 09 June 2021, 7am PDT, 10am EDT, 4pm CEST cells with dramatic implications on the validity of past cell culture related research. The fact that at least 509 cell lin...
JUN 22, 2021 10:00 AM PDT
C.E. CREDITS
JUN 22, 2021 10:00 AM PDT
Date: June 22, 2021 Time: 10:00am (PDT), 1:00pm (EDT) Antimicrobial resistance (AMR) has emerged as one of the principal public health problems of the 21st century. It threatens the effectiv...
AUG 21, 2013 10:00 AM PDT

Azole resistance in Aspergillus fumigatus - clinical isolate screening, culture selection, and genetics

C.E. Credits: CE

No demographic data is available yet for this event.


Show Resources
Loading Comments...
Show Resources