RNA polymerase mutations cause cephalosporin resistance in clinical Neisseria gonorrhoeae isolates

Elife. 2020 Feb 3:9:e51407. doi: 10.7554/eLife.51407.


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, some isolates 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 cause 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.

Keywords: Neisseria gonorrhoeae; antibiotic resistance; antimicrobial resistance; cephalosporins; gonorrhea; infectious disease; microbiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / genetics
  • Cephalosporin Resistance / genetics*
  • Cephalosporins / pharmacology
  • DNA-Directed RNA Polymerases / genetics*
  • Genes, Bacterial
  • Microbial Sensitivity Tests
  • Mutation, Missense*
  • Neisseria gonorrhoeae / drug effects*
  • Neisseria gonorrhoeae / genetics


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Cephalosporins
  • DNA-Directed RNA Polymerases

Associated data

  • SRA/SRR3360905