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Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2

Award Number: R01AI164794
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: 03/10/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2 - Project Summary Neisseria gonorrhoeae, the causative agent for the sexually transmitted infection gonorrhea, is responsible for over 800,000 infections annually in the U.S. and 78 million cases worldwide. Untreated or untreatable infections can lead to infertility, pelvic inflammatory disease (PID) in females, gonococcal arthritis in both sexes, and an increased risk of both contracting and transmitting HIV. Over the past several decades, the inexorable increase of resistance in this organism toward multiple classes of antibiotics has severely limited treatment options for gonococcal infections. Most alarmingly, resistance against the extended-spectrum cephalosporin (ESC) ceftriaxone poses a serious threat to public health. This situation requires an understanding of antibiotic resistance at the molecular level in order to enable design of new antimicrobials. ESC resistance of N. gonorrhoeae is conferred by mutated forms of penicillin-binding protein 2 (PBP2). In this application, we propose to elucidate the molecular mechanism of resistance, with the overarching hypothesis that mutations in PBP2 restrict the molecular dynamics of the protein. It builds upon our recent understanding of the interactions made by wild-type PBP2 when bound by ESCs and how conformational changes associated with binding and acylation appear restricted in PBP2 derived from ESCR strains. The investigation comprises three aims: Specific Aim 1 is a structure-function analysis of wild-type PBP2 to investigate the importance of specific interactions formed when PBP2 is bound and acylated by cephalosporins. In Specific Aim 2, we will elucidate how key mutations present in PBP2 from ESCR strains of N. gonorrhoeae reduce inactivation by cephalosporins while retaining sufficient biological function to support growth of the organism. Finally, Specific Aim 3 will examine the behavior of PBP2 variants in solution to determine whether mutations hinder protein dynamics. By revealing the molecular mechanisms of how mutations in PBP2 overcome the lethal action of β-lactams, these investigations will enable new strategies for the development of replacement anti-gonococcal agents.


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 = $696,185 )
2025	2025	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Allergy and Infectious Diseases Research	000	4	2/13/2025	NON-COMPETING CONTINUATION	$696,185
														Subtotal = $696,185

Issue Date FY: 2024 ( Subtotal = $696,246 )
2024	2024	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$69,624
2024	2024	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Allergy and Infectious Diseases Research	000	3	2/16/2024	NON-COMPETING CONTINUATION	$626,622
														Subtotal = $696,246

Issue Date FY: 2023 ( Subtotal = $697,600 )
2023	2023	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Allergy and Infectious Diseases Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$697,600
														Subtotal = $697,600

Issue Date FY: 2022 ( Subtotal = $728,298 )
2022	2022	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Allergy and Infectious Diseases Research	000	1	3/10/2022	NEW	$728,298
														Subtotal = $728,298

Grand Total All Awards = $2,818,329

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Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2

Award Number: R01AI164794

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: 03/10/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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