*Applications will be reviewed on a rolling-basis.
A research opportunity is currently available in the Office of Vaccines Research and Review (OVRR) at the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA) in Silver Spring, Maryland.
Clostridium difficile is the leading cause of hospital acquired infectious diarrhea. This project focuses on examining mechanisms of pathogenesis to identify putative targets for the development of novel therapeutics against C. difficile infection. Preliminary work has identified several targets of interest relating to iron acquisition and oxygen sensitivity. The first area of interests involves identification of mechanisms of iron acquisition that are used by C. difficile during mammalian infection. Although mammals have developed mechanisms to tightly control the availability of iron, it is a vital nutrient for nearly all bacterial species. As such, bacterial pathogens have evolved specialized mechanisms of acquiring iron from the host, including ferrous iron transporters, heme binding, and siderophores. The second area of interest involves oxygen sensitivity. Although C. difficile is generally considered a strict anaerobe, it likely encounters low levels of oxygen in the host during normal infection. In the laboratory setting, C. difficile is capable of growth in broth when exposed to an environment containing 2% oxygen. Transcriptional profiling has been performed for each of these conditions and multiple targets have been identified. The selected participant will work toward understanding the role of these genes and their potential to be the targets of novel therapeutics.
Initial efforts on this project will focus on creating clean deletion mutants in genes of interest identified from the gene expression data. However, one of the challenges associated with studying C. difficile is the lack of genetic tools due to the limitations of antibiotic selection and anaerobic growth. The lab has adapted the I-SceI mediated allelic exchange for C. difficile, which provides a promising step forward in our ability to genetically manipulate this organism. Using this new method of allelic exchange, the fellow will be able to create mutants in C. difficile and analyze the resulting phenotypes providing insight into mechanisms of C. difficile pathogenies. In addition, a CRISPR/Cas9 mediated genetic system has recently been published for genetic manipulation of C. difficile. The laboratory has obtained this system from our collaborators and will incorporate this into our studies. As things progress with these two systems, the fellow will assist in further development of genetic tools as needed to make these broadly applicable to all C. difficile clinical isolates. This portion of the project will provide new tools for studying C. difficile biology, which are expected to advance C. difficile research.
Additionally, this project will include initial efforts to isolate bacteriophage that target C. difficile from environmental water sources from multiple locations around the world. These phage will be used both in our efforts to create improved genetic tools and also in projects assessing the potential of bacteriophage therapy to target and clear intestinal bacterial pathogens.
Anticipated Appointment Start Date: Winter 2021; start date is flexible
This program, administered by ORAU through its contract with the U.S. Department of Energy to manage the Oak Ridge Institute for Science and Education, was established through an interagency agreement between DOE and FDA. The initial appointment is for six months, but may be renewed an additional year upon recommendation of FDA contingent on the availability of funds. The participant will receive a monthly stipend commensurate with educational level and experience. Proof of health insurance is required for participation in this program. The appointment is full-time at FDA in the Silver Spring, Maryland, area. Participants do not become employees of FDA, DOE or the program administrator, and there are no employment-related benefits.
If you have questions, send an email to ORISE.FDA.CBER@orau.org. Please include the reference code for this opportunity (FDA-CBER-2022-02) in your email.