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Mechanism of Antibiotic Substrate Translocation in Bacterial RND Family Efflux Pumps

Award Number: F31AI189080
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 09/30/2027

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Mechanism of Antibiotic Substrate Translocation in Bacterial RND Family Efflux Pumps - PROJECT SUMMARY/ ABSTRACT Antibiotic resistance is a growing global threat with nearly three million infections associated with antibiotic- resistant bacteria and >35,000 annual deaths from such infections in the US alone. Among these threats, Pseudomonas aeruginosa poses a serious challenge to hospitalized (e.g., those that are intubated and mechanically ventilated), post-surgical and immunocompromised individuals (e.g., in cancer and HIV), as well as those with lung infections due to genetic disorders such as Cystic Fibrosis. A major problem in treating P. aeruginosa, and many other Gram-negative infections, is its high intrinsic resistance to antibiotics, including through the action of multiple genome-encoded efflux systems. P. aeruginosa encodes a total of 12 efflux pumps of the Resistance-Nodulation-Division (RND) family, at least four of which contribute to intrinsic resistance to many clinically important antibiotics such as aminoglycosides. RND efflux systems are tripartite protein complexes, e.g., P. aeruginosa MexXY-OprM, comprising an inner membrane-embedded transporter protein (e.g., MexY), a periplasmic adaptor protein (PAP; e.g., MexX) and an outer membrane protein (OMP; e.g., OprM). P. aeruginosa RND pumps have overlapping but distinct antibiotic substrate profiles with the MexXY transporter-PAP complex being unique in its ability to efflux aminoglycosides. Furthermore, some transporter- PAP complexes have a specific OMP partner, while others combine with more than one (e.g., MexXY binds OprM and OprA). Published and preliminary data from our lab suggest that MexY has multiple potential entry sites for antibiotic substrate uptake. However, the paths followed by substrates through MexY via MexX to the OMP and the consequences of different OMP association with the transporter-PAP complex on the efflux process are unknown. For this reason, detailed structural and functional studies are urgently needed to define efflux pathways will enable inhibitor design with better target specificity and hence decreased off-target effects. In this project, I will test my overall hypothesis that efflux substrates follow a specific pathway through the assembled RND efflux system and that the efflux pathway(s) depend on the outer membrane protein identity. I will test this hypothesis in two complementary Specific Aims. Aim 1–I will determine the pathway through which antibiotic substrates are translocated out of the RND transporter protein MexY using molecular dynamics simulations complemented with functional assays and high-resolution structural studies. Aim 2–I will define the interdependency between the OMP and the antibiotic substrate efflux pathway within MexY using a combination of molecular dynamics simulations, functional assays, and high-resolution structural studies. Defining the efflux pathways used by antibiotic substrates will enhance our understanding of how the MexXY-OprM/A pumps confer high levels of aminoglycoside antibiotic resistance. Such insights will set the stage for future structure- and computational-guided development efflux pump inhibitors while establishing protocols that can be used to study other efflux pumps that contribute to resistance to other antibiotic classes.


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 = $55,114 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	4/17/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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Mechanism of Antibiotic Substrate Translocation in Bacterial RND Family Efflux Pumps

Award Number: F31AI189080

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 09/30/2027

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