Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Development of Antibiotic Adjuvants to Avert Resistance Conferred by Cfr, a Radical S-Adenosylmethionine Methylase

Award Number: R21AI180902
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2026

Group Awards By:

View Award Description

Development of Antibiotic Adjuvants to Avert Resistance Conferred by Cfr, a Radical S-Adenosylmethionine Methylase - Project Summary/Abstract Prevalent multidrug-resistant bacteria remain a significant threat to human health. About 1 million people, including 214,000 newborn babies, die annually from such infections. Most antibiotics typically target essential cellular components, enacting a high selective pressure that forces bacteria to develop resistance. This factor, among others, led to dire statistical projections citing 10 million annual deaths by 2050, prompting a call-to- action directed at tackling resistance through novel strategies. The most prominent bacterial resistance mechanisms include genetically encoded efflux pumps, structural modification of antibiotics, or modification of their molecular targets. Many target modification events follow well-established mechanisms catalyzed by enzymes. For example, the documented loss of activity by multiple classes of antibiotics that target protein synthesis is attributed to modification of ribosomal RNA (rRNA) through methylation by S-adenosylmethionine (SAM)-dependent methylases. The Chloramphenicol-florfenicol resistance (Cfr) protein is a radical SAM- dependent enzyme that catalyzes the methylation of adenosine 2503 (A2503) of 23S rRNA in the large subunit of bacterial ribosomes, conferring resistance to several classes antibiotics that inhibit translation. The gene encoding Cfr is found on naturally occurring plasmids across multiple pathogenic bacteria including Staphylococcus, Clostridium, Enterococcus, Listeria, and Bacillus species. This proposal focuses on developing compounds that inhibit the activity of Cfr, thereby preventing bacteria from acquiring resistance through rRNA methylation by this enzyme. These inhibitors will act as adjuvants that lack antibacterial activity but can restore the activity of antibiotics affected by this resistance mechanism, when administered in combination. Cfr inhibitors will be identified using a target-based approach involving computer-aided screens to be conducted with virtual libraries of over 120 million commercially available compounds using the Autodock Vina software. Compounds predicted to bind Cfr will be tested for their ability to bind the purified enzyme in vitro using Temperature Related Intensity Change measurements and evaluated for their capacity to inhibit Cfr-mediated methylation of a synthesized rRNA substrate in standard enzyme assays. Promising compounds will then be tested in an E. coli resistance evolution model to assess the inhibition of Cfr activity in bacterial cells by monitoring the antibacterial properties of antibiotics whose activity is abolished by the methylation of A2503. When used in combination, compounds that block the activity of Cfr will result in restored antibiotic activity, killing the bacterial cells. Inhibitors with this property will be co-crystallized with the enzyme to identify their binding sites, and potential mechanism of inhibition of Cfr activity. These structural data will also be used in the design of novel inhibitors with optimized binding affinities and adjuvant properties through fragment-based drug discovery techniques and structure-activity relationship studies. Optimized adjuvants will be tested against clinical isolates of bacterial species that employ this form of resistance mechanism.


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 = $238,275 )
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	001	2	8/11/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	2	1/13/2025	NON-COMPETING CONTINUATION	$238,275
														Subtotal = $238,275

Issue Date FY: 2024 ( Subtotal = $198,284 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	1	12/15/2023	NEW	$178,456
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	001	1	6/6/2024	NEW	$19,828
														Subtotal = $198,284

Grand Total All Awards = $436,559

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Development of Antibiotic Adjuvants to Avert Resistance Conferred by Cfr, a Radical S-Adenosylmethionine Methylase

Award Number: R21AI180902

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer