RNA polymerase mutations cause cephalosporin resistance in clinical Neisseria gonorrhoeae isolates

Abstract
Data availability
Article and author information
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Abstract

Increasing Neisseria gonorrhoeae resistance to ceftriaxone, the last antibiotic recommended for empiric gonorrhea treatment, poses an urgent public health threat. However, the genetic basis of reduced susceptibility to ceftriaxone is not completely understood: while most ceftriaxone resistance in clinical isolates is caused by target site mutations in penA, others lack these mutations. We show that penA-independent ceftriaxone resistance has evolved multiple times through distinct mutations in rpoB and rpoD. We identify five mutations in these genes that each increase resistance to ceftriaxone, including one mutation that arose independently in two lineages, and show that clinical isolates from multiple lineages are a single nucleotide change from ceftriaxone resistance. These RNA polymerase mutations result in large-scale transcriptional changes without altering susceptibility to other antibiotics, reducing growth rate, or deranging cell morphology. These results underscore the unexpected diversity of pathways to resistance and the importance of continued surveillance for novel resistance mutations.

Data availability

Sequencing data have been deposited in the NCBI SRA database under accession number PRJNA540288.

The following data sets were generated

1. Palace SG
2. Wang Y
3. Grad YH
(2019) N. gonorrhoeae isolates with reduced ceftriaxone susceptibility
SRA, PRJNA540288.

https://www.ncbi.nlm.nih.gov/bioproject/PRJNA540288/

The following previously published data sets were used

1. Grad YH
2. Kirkcaldy RD
3. Trees D
4. Dordel J
5. Harris SR
6. Goldstein E
7. Weinstock H
8. Parkhill J
9. Hanage WP
10. Bentley S
11. Lipsitch M
(2013) Emergence and spread of antibiotic resistant Neisseria gonorrhoeae in the US
ENA, PRJEB2999.

https://www.ebi.ac.uk/ena/data/view/PRJEB2999
1. Grad YH
2. Harris SR
3. Kirkcaldy RD
4. Green AG
5. Marks DS
6. Bentley SD
7. Trees D
8. Lipsitch M
(2016) Extended_genomic_epidemiology_of_Neisseria_gonorrhoeae_with_reduced_susceptibility_to_extended_spectrum_cephalosporins_and_azithromycin_in_the_US
ENA, PRJEB7904 and PRJEB2090.

https://www.ebi.ac.uk/ena/data/view/PRJEB7904
1. De Silva D
2. Peters J
3. Cole K
4. Cole MJ
5. Cresswell F
6. Dean G
7. Dave J
8. Thomas D Rh
9. Foster K
10. Waldram A
11. Wilson DJ
12. Didelot X
13. Grad YH
14. Crook DW
15. Peto TEA
16. Walker AS
17. Paul J
18. Eyre DW
(2016) Whole-genome sequencing to determine Neisseria gonorrhoeae transmission: an observational study.
NCBI SRA, SRR3360905.

https://www.ncbi.nlm.nih.gov/sra/?term=SRR3360905

Article and author information

Author details

Samantha G Palace

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7849-8078
Yi Wang

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Daniel H F Rubin

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Michael A Welsh

Department of Microbiology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8268-6285
Tatum D Mortimer

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Kevin Cole

Public Health England, Royal Sussex County Hospital, Brighton, United Kingdom

Competing interests
The authors declare that no competing interests exist.
David W Eyre

Big Data Institute, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Suzanne Walker

Department of Microbiology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Yonatan H Grad

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States

For correspondence
ygrad@hsph.harvard.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5646-1314

Funding

Richard and Susan Smith Family Foundation

Yonatan H Grad

National Institutes of Health (R01 AI132606)

Yonatan H Grad

National Institutes of Health (R01 GM76710)

Suzanne Walker

National Institutes of Health (F32 GM123579)

Michael A Welsh

National Institutes of Health (T32 GM007753)

Daniel H F Rubin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.