title: Genetics of chromosomally mediated intermediate resistance to ceftriaxone and cefixime in Neisseria gonorrhoeae.
abstract: All strains of Neisseria gonorrhoeae with reduced susceptibility to ceftriaxone and cefixime (cephalosporin-intermediate-resistant [Ceph(i)] strains) contain a mosaic penA allele encoding penicillin-binding protein 2 (PBP 2) with nearly 60 amino acid differences compared to the sequence of wild-type PBP 2, together with a set of resistance determinants (i.e., mtrR, penB, and/or ponA1) that are required for high-level penicillin resistance. To define the individual contributions of these determinants to reduced susceptibility to ceftriaxone and cefixime, we created isogenic strains containing the mosaic penA allele from the Ceph(i) strain 35/02 (penA35) together with one or more of the other resistance determinants and determined the MICs of penicillin G, ceftriaxone, and cefixime. The majority of cefixime resistance is conferred by the penA35 allele, with only a small contribution coming from mtrR and penB, whereas ceftriaxone resistance is nearly equally dependent upon mtrR and penB. Unlike high-level penicillin resistance, the ponA1 allele does not appear to be important for Ceph(i). A strain containing all four determinants has increased resistance to ceftriaxone and cefixime but not to the levels that the donor Ceph(i) strain does, suggesting that Ceph(i) strains, similar to high-level-penicillin-resistant strains, contain an additional unknown determinant that is required to reach donor levels of resistance. Our data also suggest that the original Ceph(i) strains arose from the transformation of penA genes from commensal Neisseria species into a penicillin-resistant strain already harboring mtrR, penB, ponA1, and the unknown gene(s) involved in high-level penicillin resistance.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
authors.forename: Shuqing
authors.initials: S
authors.lastname: Zhao
authors.forename: Margaret
authors.initials: M
authors.lastname: Duncan
authors.forename: Joshua
authors.initials: J
authors.lastname: Tomberg
authors.forename: Christopher
authors.initials: C
authors.lastname: Davies
authors.forename: Magnus
authors.initials: M
authors.lastname: Unemo
authors.forename: Robert A
authors.initials: RA
authors.lastname: Nicholas
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D020682:Cefixime / Q000494:pharmacology*; D002443:Ceftriaxone / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics / Q000502:physiology; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000235:genetics; D010403:Penicillin Resistance / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002443:Ceftriaxone; D020682:Cefixime