Saturday, November 23, 2024 11/23/2024

Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae

Award Number: R01AI132606
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT The rise of antibiotic resistant bacteria poses a grave threat to public health. To outcompete susceptible bacteria and increase in prevalence, resistant strains must mitigate fitness costs incurred by resistance- conferring mutations and genes. However, not every strain of a bacterial species can acquire and maintain genetic determinants of resistance equally well, yielding a complex evolutionary landscape between susceptibility and resistance. Elucidating the nature and diversity of the mechanisms that support acquisition and maintenance of resistance will allow us to understand how resistant strains emerge and spread and thereby accelerate development of desperately needed new strategies to prevent and treat resistant infections. We focus on the clinically important pathogen Neisseria gonorrhoeae (the gonococcus), given its high burden of disease (nearly 700,000 reported cases in the US in 2021), the imminent threat of untreatable infection, and the ease of experimental manipulation. Our goal is to define the genetic networks that support acquisition and maintenance of resistance to the most clinically important antibiotics for N. gonorrhoeae treatment: the last approved antibiotic, ceftriaxone; ciprofloxacin, for which rapid diagnostics for directed therapy are approved in Europe; and the two drugs in Phase 3 trials, zoliflodacin and gepotidacin. To do so, we will leverage a dataset that includes genome sequences and antibiotic susceptibility profiles for ~18,000 clinical isolates and a library of hundreds of selected clinical isolates, representing the species diversity. We will use computational and experimental methods, including population genetics and statistical tools to identify genetic differences in sub- populations; high-throughput bar-coded library and experimental evolution to define the loci that impact resistance acquisition as a function of genetic background; genome manipulation to validate links between genotype and resistance phenotype; and mechanistic studies to elucidate how these genetic loci influence the fitness landscape between susceptibility and resistance. We expect that the results from these studies will define the stepping-stone mutations that contribute to acquisition and maintenance of resistance to the antibiotics of highest clinical importance in N. gonorrhoeae. These results can be applied to improving clinical management strategies and public health surveillance efforts. Moreover, the system we establish here can be used to further probe the biology of N. gonorrhoeae and provides a framework for the development of similar systems to dissect the genetic networks of resistance in other bacterial pathogens.


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 = $469,104 )
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	7	5/20/2024	NON-COMPETING CONTINUATION	$469,104
2024	2023	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	6	4/18/2024	COMPETING CONTINUATION	$182
2024	2021	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	4/18/2024	NON-COMPETING CONTINUATION	-$182
														Subtotal = $469,104

Issue Date FY: 2023 ( Subtotal = $478,500 )
2023	2023	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	6	6/14/2023	COMPETING CONTINUATION	$478,500
2023	2021	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	6/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $478,500

Issue Date FY: 2021 ( Subtotal = $398,750 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	6/23/2021	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2020 ( Subtotal = $398,750 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	6/12/2020	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2019 ( Subtotal = $398,750 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	6/24/2019	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2018 ( Subtotal = $398,750 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/14/2018	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2017 ( Subtotal = $397,500 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	6/15/2017	NEW	$397,500
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	6/19/2017	NEW	$0
														Subtotal = $397,500

Grand Total All Awards = $2,940,104

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Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae

Award Number: R01AI132606

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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