# Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2024 · $469,104

## Abstract

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.

## Key facts

- **NIH application ID:** 10867488
- **Project number:** 5R01AI132606-07
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Yonatan H Grad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $469,104
- **Award type:** 5
- **Project period:** 2017-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867488

## Citation

> US National Institutes of Health, RePORTER application 10867488, Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae (5R01AI132606-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10867488. Licensed CC0.

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