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

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2021 · $398,750

## 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 be able to compensate for fitness costs incurred by
resistance-conferring mutations and genes. However, not every strain of a bacterial species can compensate
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 use the clinically important pathogen Neisseria gonorrhoeae (the gonococcus) as a model system, given
its high burden of disease (820,000 cases in the US and nearly 80 million cases globally each year), 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 three of the clinically most
important antibiotics for treatment of gonococcus: the extended spectrum cephalosporins, azithromycin, and
the quinolones. To do so, we will leverage our unique dataset of >1100 epidemiologically and genetically
diverse clinical gonococcal isolates for which we have full genome sequences and antibiotic susceptibility
profiles. We will use population-based computational and experimental methods that incorporate the diversity
of susceptible and resistant populations and thus represent a fundamental shift from single reference strain
studies. These methods include unbiased statistical tools to identify genetic differences in sub-populations;
high-throughput transposon mutagenesis screens to define the loci that impact resistance as a function of
genetic background; and a system for genome manipulation to validate links between genotype and resistance
phenotype.
We expect that the results from these studies will define the interacting loci that contribute to resistance in
natural populations. These results can be applied to improving public health surveillance efforts and
development of therapeutics. Moreover, the system we establish here can be used to further probe the biology
of gonococcus and provides a framework for the development of similar systems to dissect of the genetic
networks of resistance in other bacterial pathogens.

## Key facts

- **NIH application ID:** 10190792
- **Project number:** 5R01AI132606-05
- **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:** 2021
- **Award amount:** $398,750
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190792

## Citation

> US National Institutes of Health, RePORTER application 10190792, Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae (5R01AI132606-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10190792. Licensed CC0.

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