K43TW012786
Project Grant
Overview
Grant Description
Mycobacterial epigenetics: Investigating the impact of DNA methylation on antibiotic tolerance and persistence - Project summary
Sterilization of tuberculosis (TB) requires lengthy chemotherapy treatment to eradicate persister Mycobacterium tuberculosis (MTB) sub-populations.
Persister MTB are unaffected by anti-TB treatment due to their viable but non-replicating (VBNR) or slowly replicating state in the absence of heritable genetic changes.
Persistence is a reversible phenotype which may be regulated by epigenetic mechanisms.
DNA methylation contributes to the formation of persister bacteria in other bacterial species, but the role for DNA methylation remains unknown in MTB persister formation.
The objective of this K43 award is to establish the role of DNA methylation in the MTB stress response and in the formation of MTB heterogeneity, which includes the persister sub-population.
The primary mentorship of Drs. Sampson (LMIC primary mentor) and Aldrige (USA primary mentor), both experienced in mycobacteriology, will provide critical career advancement training.
Drs. Sampson and Aldridge have both contributed to advancing our understanding of MTB population heterogeneity by developing a replication reporter plasmid for the identification of MTB persisters and a microfluidic imaging platform to investigate cell-to-cell heterogeneity, respectively.
This project will build on these advances to address two specific aims: (1) Demonstrate a role for DNA methylation in the MTB stress response and phenotypic drug resistance, and (2) Demonstrate a role for DNA methylation in MTB persistence and antibiotic tolerance.
This study will for the first time show that DNA methylation results in changes on a protein level.
We will show that DNA methylation is used by MTB to respond to environmental stress and promote the formation of a persister sub-population.
Phenotypic drug susceptibility testing and killing assays will assess the impact of DNA methylation on the ability of MTB to tolerate antibiotic exposure.
Population and single-cell imaging analysis will assess the impact of DNA methylation on MTB population heterogeneity, which has previously been shown to impact treatment efficacy.
At the end of this K43-funded mentored study, the applicant will establish herself as an independently funded TB research scientist and group leader at Stellenbosch University.
Interdisciplinary collaborations established during this award will lay the foundation for future investigations into the prevention of MTB persisters for shorter TB treatment, the identification of biomarkers for diagnosis of persister infections, and prevention of TB recurrence.
Sterilization of tuberculosis (TB) requires lengthy chemotherapy treatment to eradicate persister Mycobacterium tuberculosis (MTB) sub-populations.
Persister MTB are unaffected by anti-TB treatment due to their viable but non-replicating (VBNR) or slowly replicating state in the absence of heritable genetic changes.
Persistence is a reversible phenotype which may be regulated by epigenetic mechanisms.
DNA methylation contributes to the formation of persister bacteria in other bacterial species, but the role for DNA methylation remains unknown in MTB persister formation.
The objective of this K43 award is to establish the role of DNA methylation in the MTB stress response and in the formation of MTB heterogeneity, which includes the persister sub-population.
The primary mentorship of Drs. Sampson (LMIC primary mentor) and Aldrige (USA primary mentor), both experienced in mycobacteriology, will provide critical career advancement training.
Drs. Sampson and Aldridge have both contributed to advancing our understanding of MTB population heterogeneity by developing a replication reporter plasmid for the identification of MTB persisters and a microfluidic imaging platform to investigate cell-to-cell heterogeneity, respectively.
This project will build on these advances to address two specific aims: (1) Demonstrate a role for DNA methylation in the MTB stress response and phenotypic drug resistance, and (2) Demonstrate a role for DNA methylation in MTB persistence and antibiotic tolerance.
This study will for the first time show that DNA methylation results in changes on a protein level.
We will show that DNA methylation is used by MTB to respond to environmental stress and promote the formation of a persister sub-population.
Phenotypic drug susceptibility testing and killing assays will assess the impact of DNA methylation on the ability of MTB to tolerate antibiotic exposure.
Population and single-cell imaging analysis will assess the impact of DNA methylation on MTB population heterogeneity, which has previously been shown to impact treatment efficacy.
At the end of this K43-funded mentored study, the applicant will establish herself as an independently funded TB research scientist and group leader at Stellenbosch University.
Interdisciplinary collaborations established during this award will lay the foundation for future investigations into the prevention of MTB persisters for shorter TB treatment, the identification of biomarkers for diagnosis of persister infections, and prevention of TB recurrence.
Awardee
Funding Goals
THE JOHN E. FOGARTY INTERNATIONAL CENTER (FIC) SUPPORTS RESEARCH AND RESEARCH TRAINING TO REDUCE DISPARITIES IN GLOBAL HEALTH AND TO FOSTER PARTNERSHIPS BETWEEN U.S. SCIENTISTS AND THEIR COUNTERPARTS ABROAD. FIC SUPPORTS BASIC BIOLOGICAL, BEHAVIORAL, AND SOCIAL SCIENCE RESEARCH, AS WELL AS RELATED RESEARCH TRAINING AND CAREER DEVELOPMENT. THE RESEARCH PORTFOLIO IS DIVIDED INTO SEVERAL PROGRAMS THAT SUPPORT A WIDE VARIETY OF FUNDING MECHANISMS TO MEET PROGRAMMATIC OBJECTIVES.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
South Africa
Geographic Scope
Foreign
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 101% from $106,160 to $213,174.
Stellenbosch University was awarded
MTB DNA Methylation Impact on Antibiotic Tolerance
Project Grant K43TW012786
worth $213,174
from Fogarty International Center in September 2024 with work to be completed primarily in South Africa.
The grant
has a duration of 5 years and
was awarded through assistance program 93.989 International Research and Research Training.
The Project Grant was awarded through grant opportunity Emerging Global Leader Award (K43 Independent Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 9/24/25
Period of Performance
9/1/24
Start Date
8/31/29
End Date
Funding Split
$213.2K
Federal Obligation
$0.0
Non-Federal Obligation
$213.2K
Total Obligated
Activity Timeline
Transaction History
Modifications to K43TW012786
Additional Detail
Award ID FAIN
K43TW012786
SAI Number
K43TW012786-2387051190
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Non-Domestic (Non-U.S.) Entity
Awarding Office
75NF00 NIH Fogarty International Center
Funding Office
75NF00 NIH Fogarty International Center
Awardee UEI
C6CHDMTANVS3
Awardee CAGE
SZ208
Performance District
Not Applicable
Modified: 9/24/25