Revealing the underpinnings of antifungal resistance and advancing treatment of invasive fungal infections
Fungal infections present a significant clinical challenge, particularly for immune-compromised patients, and are responsible for more than one million life-threatening infections each year. Currently there are only three distinct classes of primary antifungals available for clinical application, and many pathogens exhibit acquired or inherent resistance to agents from one or more classes, further threatening the vulnerable populations of patients most affected by these infections. Our lab is interested in 1) understanding the mechanisms that drive antifungal resistance, 2) building the tools needed to study and manipulate various fungal pathogens, and 3) developing improved and novel therapeutic approaches for the treatment of patients with invasive fungal infections.
Understanding resistance mechanisms of fungal pathogens
In continued collaborations with an international team of investigators, including faculty in the Department of Pharmacy and Pharmaceutical Sciences at St. Jude and at UTHSC, our laboratory explores the mechanisms of antifungal resistance in important fungal pathogens including Candida auris, Aspergillus fumigatus, and most recently, Mucorales. We are particularly interested in antifungal resistance mechanisms limiting the utility of front-line therapies, such as the echicocandins for the treatment of invasive Candida auris infections, and amphotericin B for the treatment of Mucorales infections. Moreover, as Mucorales exhibit features of inherent resistance to multiple antifungal agents, we are motivated us to interrogate the intrinsic mechanisms that mediate this phenomenon in an effort to assist in the development of therapeutic strategies to overcome infections caused by these organisms.
Developing and adapting technologies for the study of fungal pathogens
While gene-editing technologies continue to evolve, most approaches are designed for application in model organisms or human cell lines. Fungal pathogens present unique limitations related to genetic tractability and require organism-adapted tools and approaches. We have been focused on optimizing CRISPR/Cas9-based gene-editing systems for use in our fungal pathogens of interest, and have been successful in developing novel strategies which expand our genetic and molecular capabilities. Employing our Candida auris-adapted gene-editing system, it is now possible to to perform true single base -editing to explore the impact of individual nucleotide substitutions of interest, and we continue to refine and adapt cutting-edge approaches to the genetic and molecular study this emerging public health threat. Currently, we’re working with the Center for Advanced Genome Engineering at St. Jude to implement high efficiency screening of 70 different fungal-specific transcription factors in Candida auris in the hopes of creating a library of knockout strains for characterization and analysis.
Developing antifungal therapeutic strategies
We are interested in improving therapeutic targeting of fungal pathogens both by enhancing activity of existing antifungal agents and identifying brand new molecular entities with antifungal activity. Using analogous but unique approaches adapted for each organism of interest, our work is focused primarily on Candida auris, Aspergillus fumigatus, and Mucorales. We have developed high throughput screening assays, with optimized reliability and safety, to evaluate the extensive libraries of FDA-approved and novel chemical compounds available at St. Jude. This approach has revealed exploitable vulnerabilities in Candida auris and Aspergillus fumigatus – and we are now working on therapeutics targeted to achieve avirulence and hyper-susceptibility in these pathogens. Mucorales requires more fundamental investigation – as it this group of molds is less well characterized – but we plan to apply the same approach to advance drug discovery applicable to this devastating group of fungal pathogens. Our work benefits from extensive collaborations with the Department of Chemical Biology and Therapeutics, various St. Jude core facilities, and drug development groups at the NIH.
Clinical pharmacy initiatives
As a clinician-scientist specializing in infectious diseases pharmacotherapy, Dr. Rybak is involved in several initiatives and efforts in collaboration with the clinical pharmacy and infectious diseases teams at St. Jude. Through these interactions, he has contributed to the development of clinical practice guidelines relevant to the use of antifungal agents for St. Jude patients, and assists in the design, evaluation, and therapeutic drug monitoring of antimicrobial therapies. Furthermore, as a member of the Antimicrobial Utilization and Improvement Committee team, Dr. Rybak also contributes to antimicrobial stewardship initiatives a St. Jude, and seeks to maximize the safety and efficacy of antimicrobial therapies for all patients.
Dr. Jeffrey M. Rybak currently serves as an Instructor in the Department of Pharmacy and Pharmaceutical Sciences at St. Jude. His robust pedigree includes a PharmD from Eugene Applebaum College of Pharmacy, dual residency training in Pharmacy Practice and Infectious Disease at the University of Kentucky, followed by PhD and postdoc training at UTHSC. Dr. Rybak is part of a collaborative team of researchers interested in mechanisms of antifungal resistance and development of novel therapeutic approaches for fungal infections. He balances his time in the lab with his clinical pharmacy practice and has contributed to the development and adoption of antimicrobial use guidelines at St. Jude. He looks forward to expanding his research program and welcomes the opportunity to mentor trainees across his areas of expertise.
Students and postdocs who are passionate and motivated, with backgrounds or great interest in pharmacology, molecular genetics, mycology, or high throughput screening and drug discovery will be welcome additions to the Rybak laboratory.