Elucidating the biophysical basis of repeatability in the evolution of drug resistance
Active Project Grant Awarded Last action
- Award ID
- F31AI200462
- Recipient
-
The Regents Of The University Of California. San Francisco UEI KMH5K9V7S518
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $88,000
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 2% complete
- Originally
- Place of performance
- San Francisco, CA 94143, USA
Award details come from USAspending.gov.
Description
- Abstract
- Antimicrobial resistance is a pervasive threat to society, and our ability to overcome IT has been hampered by the plethora of resistance mutations acquired by pathogens. This proposal aims to quantify how repeatable drug resistance pathways are across distinct species of a model pathogen and elucidate the biophysics underlying the repeatability. Ultimately, we need to gain a mechanistic understanding of why drug resistance varies across distinct genetic backgrounds to design broadly effective inhibitors. Drug resistance is constrained by the biophysical effects of mutations, as adaptive mutations often compromise properties like catalysis and stability. Mutations can also have distinct effects on fitness (or growth) across different species. However, IT is not known how the biophysical effects of mutations vary across homologous proteins in species of a pathogen, which is necessary to understand why they traverse different drug resistance pathways. To address this GAP, I will utilize the enterovirus 3C protease (3CPRO) and its inhibitor rupintrivir as a model because: (a) enteroviruses have a broad phylogeny of non-pathogenic species, (B) 3CPRO is amenable to high-throughput measurement of biophysical properties like catalysis and stability, (C) rupintrivir can serve as an identical selection pressure across homologous proteins as IT engages conserved residues. I hypothesize that mutations have species-dependent effects on biophysical properties, which shape the divergence of resistance trajectories. Aim 1 will examine the repeatability of resistance pathways by passaging parallel populations of divergent 3CPRO homologs with rupintrivir and quantifying genetic and phenotypic differences of replicate adaptive trajectories. To test whether adaptive mutations are compatible across strains, bulk fitness assays will be used. Aim 2 will dissect the biophysical basis of the background-dependent effects of mutations across the 3CPRO homologs by performing high-throughput measurements of catalysis and stability on mutant libraries of the homologs. Together, these studies will reveal how repeatable evolution is across species of a model pathogen and define the biophysical mechanisms that govern that repeatability. These insights will advance efforts to predict divergent resistance strategies and guide the design of broadly effective antimicrobials. The proposed training plan and environment have been optimized to ensure I can accomplish the project and establish a successful career as an investigator. I will 1) deepen my interdisciplinary expertise through courses, seminars, and collaborations across biophysics, virology, and evolutionary biology; 2) strengthen my communication skills and broaden my scientific network through writing manuscripts, presenting posters, and participation in symposia; and 3) expand my leadership and mentoring experience by guiding high school, undergraduate, and graduate trainees. My training is further supported by the collaborative and well-resourced environment of my sponsoring lab, graduate program, and institution.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $44,000 | |
| Amendment | $44,000 | |
| Original award | $0 |
Quick answers
Who received award F31AI200462?
F31AI200462 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on October 11, 2026.
How much is award F31AI200462 worth?
$88,000 has been obligated on F31AI200462.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award