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Small Molecule Regulation of an Antibiotic Resistance Efflux Pump in Pseudomonas aeruginosa

Award Number: F31AI197847
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/10/2026
PERIOD OF PERFORMANCE END DATE: 04/09/2029

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Small Molecule Regulation of an Antibiotic Resistance Efflux Pump in Pseudomonas aeruginosa - Abstract Bacterial resistance to antibiotics is an escalating crisis in healthcare that threatens to fundamentally alter modern medicine. There are many distinct mechanisms of antibiotic resistance in bacteria, but increased production of multidrug efflux pumps is a common response among pathogenic bacteria to remove drugs from the cell. The Resistance-Nodulation-Division (RND) efflux pump superfamily is broadly distributed among Gram- negative pathogenic bacteria and contributes extensively to clinical resistance. The important opportunistic pathogen Pseudomonas aeruginosa encodes multiple RND efflux systems, at least four of which contribute to its intrinsic multi-drug resistance. A major efflux pump in P. aeruginosa is MexXY-OprM and it is the only efflux pump that can export aminoglycosides, an antibiotic that is clinically relevant in the treatment of bacterial infections. MexXY is regulated by the expression of the PA5471 operon that encodes for a regulatory leader peptide, PA5471.1, and the PA5471 protein. The PA5471.1 leader peptide and aminoglycoside exposure controls the expression of PA5471. The SuhB protein, typically known to interact with RNA polymerase as an integral part of the antitermination complex for ribosomal RNA biosynthesis in E. coli, is also involved in this regulation in the absence of aminoglycosides by preventing both ribosome stalling and protein production of PA5471. However, the molecular and structural bases of this novel gene regulation are unknown. My hypothesis is that aminoglycoside binding to the ribosome in the presence of the PA5471.1 leader peptide inhibits SuhB function and causes ribosome stalling to confer downstream gene expression of PA5471, suggesting a novel mode of gene regulation. In Aim 1, I will use reporter assays to determine the regions in the PA5471.1 leader peptide and the downstream intergenic region between PA5471.1 and PA5471 that are important for PA5471 production and thus MexXY production. I will also identify PA5471.1 leader peptide amino acids important for ribosome stalling using biochemical assays. Lastly, I will determine the structural basis of aminoglycoside-mediated ribosomal stalling in the context of actively translating PA5471.1 by cryogenic-electron microscopy. In Aim 2, I will determine the important SuhB residues for the regulation of PA5471 using reporter and biochemical assays to test whether SuhB functions as a transcription or translation factor. Finally, I will determine the structural basis of SuhB interaction with the ribosome by cryogenic-electron microscopy. Collectively, my results will reveal important aspects of P. aeruginosa antibiotic-mediated gene regulation and intrinsic antibiotic resistance. These studies will provide the foundation to identify new targets for novel antibiotic drug development to combat the increasing antibiotic resistance in P. aeruginosa.


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: 2026 ( Subtotal = $50,114 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	1	4/6/2026	NEW	$0
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	4/6/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Small Molecule Regulation of an Antibiotic Resistance Efflux Pump in Pseudomonas aeruginosa

Award Number: F31AI197847

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/10/2026

PERIOD OF PERFORMANCE END DATE: 04/09/2029

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