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Characterizing the Cyclic-di-AMP Pathway in Clostridioides difficile

Award Number: K43TW013094
ORGANIZATION: FOGARTY INTERNATIONAL CENTER
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Characterizing the Cyclic-di-AMP Pathway in Clostridioides difficile - Project summary/abstract Antimicrobial resistance (AMR) is a global public health issue. It is estimated that AMR would cause up to 10 million deaths by 2050, where south Asia and Latin America and the Caribbean being the highest overall mortality rate. AMR situation in Thailand is not better than others low- and middle-income countries (LMICs) owing to a high proportion of irrational drug use and the lack of policies in the past. Clostridioides difficile, a spore-forming, toxin-producing gram-positive, presents the threat on AMR as it is mostly multidrug resistance. C. difficile infection (CDI) can cause a wide range of symptoms ranging from severe diarrhea to life- threatening colitis. CDI is often associated with post-antibiotic exposure, therefore, it represents the major cause of nosocomial infections. Current treatment of CDI is limited to only fidaxomicin, vancomycin, and metronidazole. This urges the community to seek for novel therapeutic agents, better yet with new molecular targets. Therefore, the long-term goal of this proposed study is to explore c-di-AMP pathway as a novel drug target for C. difficile, while providing me the trainings and platform to become an independent researcher in the field of structural biology with the focus on drug mechanism study. The central hypothesis of this project is that c-di-AMP pathway is essential for bacterial osmotic homeostasis and response to environmental and antibiotic stress; and targeting this pathway is detrimental to the bacterium. The overall objectives of the study are (1) to characterize the functions and elucidate the structures of key component of the c-di-AMP receptors, TrkA and busAA, in C. difficile and (2) to identify small molecules that target these proteins as a proof-of- concept for draggability of the c-di-AMP pathway. To achieve the objectives and prove the hypothesis of this study, three specific aims will be pursued: (1) to elucidate the structure and function of c-di-AMP binding proteins involved in K+ transporter regulation by using cryo-EM technique and molecular biology/biochemistry characterizations; (2) to investigate the roles of c-di-AMP components in C. difficile physiology by generating and using knockout stains of c-di-AMP binding proteins and microbiology and biochemistry characterizations; and (3) to identify small molecule agonists for c-di-AMP binding proteins to synergize the effect of other antibiotic using virtual screening, protein characterization, and drug combination approaches. The proposed project is innovative because c-di-AMP is a recently discovered pathway and many aspects of this pathway are yet to be explored. The pathway has a potential for drug development, not just for C. difficile, but for other bacteria with limited treatment options and molecular targets. This project will also foster and incubate emerging cryo-EM research in Thailand.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $151,200 )
2025	2025	MAHIDOL UNIVERSITY	999 PHUTTAMONTHON 4 ROAD	PHUTTHAMONTHON				THA	International Research and Research Training	000	1	9/14/2025	NEW	$151,200
														Subtotal = $151,200

Grand Total All Awards = $151,200

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Characterizing the Cyclic-di-AMP Pathway in Clostridioides difficile

Award Number: K43TW013094

ORGANIZATION: FOGARTY INTERNATIONAL CENTER

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/16/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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