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Variation in supplemental carbon dioxide requirements defines lineage-specific antibiotic resistance acquisition in Neisseria gonorrhoeae

View ORCID ProfileDaniel H.F. Rubin, View ORCID ProfileKevin C. Ma, View ORCID ProfileKathleen A. Westervelt, View ORCID ProfileKarthik Hullahalli, View ORCID ProfileMatthew K. Waldor, View ORCID ProfileYonatan H. Grad
doi: https://doi.org/10.1101/2022.02.24.481660
Daniel H.F. Rubin
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Kevin C. Ma
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Kathleen A. Westervelt
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Karthik Hullahalli
2Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
3Department of Microbiology, Harvard Medical School, Boston, MA, USA
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Matthew K. Waldor
2Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
3Department of Microbiology, Harvard Medical School, Boston, MA, USA
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Yonatan H. Grad
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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  • For correspondence: ygrad@hsph.harvard.edu
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Abstract

The evolution of the obligate human pathogen Neisseria gonorrhoeae has been shaped by selective pressures from diverse host niche environments1,2 as well as antibiotics3,4. The varying prevalence of antibiotic resistance across N. gonorrhoeae lineages5 suggests that underlying metabolic differences may influence the likelihood of acquisition of specific resistance mutations6,7. We hypothesized that the requirement for supplemental CO2, present in approximately half of isolates8, reflects one such example of metabolic variation. Here, using a genome-wide association study and experimental investigations, we show that CO2-dependence is attributable to a single substitution in a β-carbonic anhydrase, canB. CanB19E is necessary and sufficient for growth in the absence of CO2, and the hypomorphic CanB19G variant confers CO2-dependence. Furthermore, ciprofloxacin resistance is correlated with CanB19G in clinical isolates, and the presence of CanB19G increases the likelihood of acquisition of ciprofloxacin resistance. Together, our results suggest that metabolic variation has impacted the acquisition of fluoroquinolone resistance.

Competing Interest Statement

YHG is on the Scientific advisory board of Day Zero Diagnostics and consults for GSK. YHG has received funding from Merck and Pfizer.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 25, 2022.
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Variation in supplemental carbon dioxide requirements defines lineage-specific antibiotic resistance acquisition in Neisseria gonorrhoeae
Daniel H.F. Rubin, Kevin C. Ma, Kathleen A. Westervelt, Karthik Hullahalli, Matthew K. Waldor, Yonatan H. Grad
bioRxiv 2022.02.24.481660; doi: https://doi.org/10.1101/2022.02.24.481660
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Variation in supplemental carbon dioxide requirements defines lineage-specific antibiotic resistance acquisition in Neisseria gonorrhoeae
Daniel H.F. Rubin, Kevin C. Ma, Kathleen A. Westervelt, Karthik Hullahalli, Matthew K. Waldor, Yonatan H. Grad
bioRxiv 2022.02.24.481660; doi: https://doi.org/10.1101/2022.02.24.481660

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