Sunday, December 22, 2024 12/22/2024

Discovering novel antimicrobial agents that target sRNA regulated antibiotic resistance mechanisms

Award Number: SC2GM136500
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The rise of antibiotic resistant pathogenic bacteria represents a major threat to human health that demands the development of new strategies to combat resistance mechanisms. A significant challenge is overcoming bacteria’s ability to limit the efficacy of antibiotics by reducing their intracellular concentration by increasing efflux out of the cell and decreasing entry through membrane proteins. One method bacteria use to induce these intrinsic resistance processes is through post-transcriptional regulation of genes by small RNAs (sRNAs). For example, the sRNA MicF represses the translation of outer membrane protein F (OmpF), a porin involved in antibiotic uptake. Transcription of MicF is known to increase due to environmental factors such as oxidative stress and the presence of antibiotics. Here we propose an innovative antimicrobial treatment strategy whereby we introduce a biomolecule designed to sequester MicF, thus increasing the efficacy of existing antibiotics by increasing antibiotic uptake through the porin OmpF. To achieve this goal, we will first characterize changes in the transcription of MicF during Escherichia coli’s response to representatives from the major classes of antibiotics (Aim 1). Next, we will pursue two parallel strategies to design biomolecules that will bind and sequester MicF in the cell. The first will be to design antisense molecules that bind directly to MicF (Aim 2). In the second strategy, we will randomize amino acids of known RNA binding peptides to change their specificity to bind to MicF (Aim 3). Initial validation will be done in E. coli; however, MicF is highly conserved in g-proteobacteria and thus results from this work can be extended to other important pathogens. We expect our designed biomolecules to increase susceptibility to a subset of antibiotics, thus reducing the impact of pathogenic bacteria on human health. Furthermore, the strategy outlined here is generalizable and can be extended to other RNA regulation mechanisms involved in antibiotic resistance.


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: 2024 ( Subtotal = -$346 )
2024	2022	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	6/12/2024	NON-COMPETING CONTINUATION	-$346
														Subtotal = -$346

Issue Date FY: 2022 ( Subtotal = $145,000 )
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	6/15/2022	NON-COMPETING CONTINUATION	$14,500
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	1/10/2022	NON-COMPETING CONTINUATION	$130,500
														Subtotal = $145,000

Issue Date FY: 2021 ( Subtotal = $145,000 )
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	2	2/17/2021	NON-COMPETING CONTINUATION	$14,500
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	1/28/2021	NON-COMPETING CONTINUATION	$130,500
														Subtotal = $145,000

Issue Date FY: 2020 ( Subtotal = $145,000 )
2020	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	3/23/2020	NEW	$145,000
														Subtotal = $145,000

Grand Total All Awards = $434,654

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Discovering novel antimicrobial agents that target sRNA regulated antibiotic resistance mechanisms

Award Number: SC2GM136500

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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