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Antimicrobial Agents and Chemotherapy, September 2009, p. 3744-3751, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00304-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Genetics of Chromosomally Mediated Intermediate Resistance to Ceftriaxone and Cefixime in Neisseria gonorrhoeae
Shuqing Zhao,1,
Margaret Duncan,1
Joshua Tomberg,1
Christopher Davies,2
Magnus Unemo,3 and
Robert A. Nicholas1*
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,1 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina,2 National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden3
Received 5 March 2009/ Returned for modification 1 May 2009/ Accepted 10 June 2009
All strains of Neisseria gonorrhoeae with reduced susceptibility to ceftriaxone and cefixime (cephalosporin-intermediate-resistant [Cephi] 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 Cephi 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 Cephi. A strain containing all four determinants has increased resistance to ceftriaxone and cefixime but not to the levels that the donor Cephi strain does, suggesting that Cephi 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 Cephi 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.
* Corresponding author. Mailing address: Department of Pharmacology, CB#7365, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365. Phone: (919) 966-6547. Fax: (919) 966-5640. E-mail: nicholas{at}med.unc.edu
Published ahead of print on 15 June 2009.
Present address: Center for Behavioral Cardiovascular Health, Division of General Medicine, Columbia University Medical Center, New York, NY 10014.
Antimicrobial Agents and Chemotherapy, September 2009, p. 3744-3751, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00304-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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