Mycobacterial pathogens are the source of a multitude of human diseases. Although usually treatable with antibiotics, poor compliance with a strict antibiotic regimen contributes to the development of drug resistant strains. Some clinically important, non-tuberculous mycobacteria (NTM), such as M. avium and M. abscessus, frequently occur in association with cystic fibrosis (CF). Infection in CF patients come with substantial side effects, including antibiotic-associated deafness and negation of the possibility of lung transplantation, as transplant-associated immunosuppression in infected patients has a high rate of mortality. Clearly, there is an urgent need for new approaches to treating mycobacterial diseases that circumvent drug resistance and other undesirable side effects.
Technology Description
Bacteriophages are viruses that parasitize bacteria, and represent a potential new paradigm in treating drug-resistant mycobacterial diseases. Phages are typically highly specific for a particular bacterial species, and often for individual strains of that species. This specificity is both a blessing and a curse: the high specificity allows efficient targeting and lowers the risk of harmful side effects, but on the other hand, a phage useful in treating one type of bacteria may not be useful for a second patient infected with a different strain. NTM strains have high genetic variability and phages must be selected carefully. Twelve phages, including phage Muddy and its derivatives, have been identified as effective in treating M. abscessus with no detectable resistance, and thus can be used alone or in two-phage cocktails to treat NTM infections with minimal risk of treatment failure due to resistance. Further, researchers have developed a method of using reporter phage derivatives with fluorescent reporter genes to rapidly determine bacterial susceptibility.Advantages
Identification of appropriate phages via reporter phage method is fast, simple, and high-throughput
Minimal resistance leads to high probability of treatment success
No immunosuppression
Minimal associated side effectsApplications
Identification of phages useful for therapy of non-tuberculosis mycobacteria infections
Treatment of highly antibiotic resistant infectionsStage of Development
In vivo dataIP Status
Provisional patent filedRelevant publications
Dedrick, R. M., Guerrero-Bustamante, C. A., Garlena, R. A., Russell, D. A., Ford, K., Harris, K., Gilmour, K. C., Soothill, J., Jacobs-Sera, D., Schooley, R. R., Hatfull, G. F. and Spencer, H. (2019). Use of engineered bacteriophages for personalized treatment of a patient with a disseminated drug resistant Mycobacterium abscessus infection. Nature Med. 25, 730-733. doi: 10.1038/s41591-019-0437-z. PMID: 31068712External Links
Hatfull Lab
InnovatorsGraham Hatfull, PhD
Eberly Family Professor of Biotechnology, HHMI Professor, Department of Biological Sciences, University of Pittsburgh
Dr. Hatfull runs the Hatfull Lab in the Department of Biological Sciences, and focuses on the molecular genetics of the mycobacteria and their associated phages. His research interests include viral diversity and evolution, genetic systems for tuberculosis, and the mechanisms of site-specific recombination. He also helps to lead the Phage Hunters Advancing Research and Education (PHIRE) and the Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) groups along with the Howard Hughes Medical Institute (HHMI).Education
Postdoctoral, Medical Research Council, UK
Postdoctoral, Yale University
PhD, University of Edinburgh, Scotland
Undergraduate, Biological Sciences, University of LondonCarlos Guerrero
Research Associate, PhD Candidate, and Operations Manager, Hatfull Lab
Carlos works in integrative systems biology to focus on advanced bioinformatics and computational skills.Education
BS, Biological Sciences, Duquesne UniversityRebekah Dedrick, PhD
Postdoctoral Research Associate, Hatfull Lab
Dr. Dedrick is interested in using genetic and molecular approaches to understand gene expression and gene function in mycobacteriophages and elucidating the mechanisms of lytic and lysogenic growth in mycobacteriophages using transcriptomic, proteomic, and gene knockout strategies.Education
PhD, Biology, Duquesne University
BS, Biology, Chem Minor, Slippery Rock UniversityHatfull Lab Publications
Mavrich, T. N. & Hatfull, G. F. (2019). Evolution of superinfection immunity in the Cluster A mycobacteriophages. mBio. In press.
Dedrick, R. M., Guerrero-Bustamante, C. A., Garlena, R. A., Russell, D. A., Ford, K., Harris, K., Gilmour, K. C., Soothill, J., Jacobs-Sera, D., Schooley, R. R., Hatfull, G. F., and Spencer, H. (2019). Use of engineered bacteriophages for personalized treatment of a patient with a disseminated drug resistant Mycobacterium abscessus infection. Nature Medicine. In press.
Montgomery, M. T., Guerrero Bustamante, C. A., Dedrick, R. M., Jacobs-Sera, D., and Hatfull, G. F. (2019). Yet more evidence of collusion: A new viral defense system encoded by Gordonia phage CarolAnn. mBio 10. pii: e02417-18
Gentile, G. M., Wetzel, K. S., Dedrick, R. M., Montgomery, M. T., Garlena, R. A., Jacobs-Sera, D., and Hatfull, G. F. (2019). More evidence of collusion: A new prophage-mediated viral defense system encoded by mycobacteriophage Sbash. mBio 10. pii: e00196-19
Hatfull, G.F. (2018). Mycobacteriophages. Microbiol Spectr. 5, doi:10.1128/microbiolspec. GPP3-0026-2018.
