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Antimicrobial Agents and Chemotherapy, March 2002, p. 769-777, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.769-777.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mutations in ponA, the Gene Encoding Penicillin-Binding Protein 1, and a Novel Locus, penC, Are Required for High-Level Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae

Patricia A. Ropp,1 Mei Hu,2 Melanie Olesky,2 and Robert A. Nicholas2*

Departments of Chemistry,1 Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-73652

Received 15 June 2001/ Returned for modification 19 September 2001/ Accepted 6 December 2001

Chromosomally mediated penicillin resistance in Neisseria gonorrhoeae occurs in part through alterations in penicillin-binding proteins (PBPs) and a decrease in outer membrane permeability. However, the genetic and molecular mechanisms of transformation of a penicillin-susceptible strain of N. gonorrhoeae to high-level penicillin resistance have not been clearly elucidated. Previous studies suggested that alterations in PBP 1 were involved in high-level penicillin resistance. In this study, we identified a single amino acid mutation in PBP 1 located 40 amino acids N terminal to the active-site serine residue that was present in all chromosomally mediated resistant N. gonorrhoeae (CMRNG) strains for which MICs of penicillin were >=1 µg/ml. PBP 1 harboring this point mutation (PBP 1*) had a three- to fourfold lower rate of acylation (k2/K') than wild-type PBP 1 with a variety of ß-lactam antibiotics. Consistent with its involvement in high-level penicillin resistance, replacement of the altered ponA gene (ponA1) in several CMRNG strains with the wild-type ponA gene resulted in a twofold decrease in the MICs of penicillin. Surprisingly, transformation of an intermediate-level penicillin-resistant strain (PR100; FA19 penA4 mtr penB5) with the ponA1 gene did not increase the MIC of penicillin for this strain. However, we identified an additional resistance locus, termed penC, which was required along with ponA1 to increase penicillin resistance of PR100 to a high level (MIC = 4 µg/ml). The penC locus by itself, when present in PR100, increases the MICs of penicillin and tetracycline twofold each. These data indicate that an additional locus, penC, is required along with ponA1 to achieve high-level penicillin resistance.

* Corresponding author. Mailing address: University of North Carolina at Chapel Hill, Department of Pharmacology, CB# 7365 Mary Ellen Jones Bldg., Chapel Hill, NC 27599-7365. Phone: (919) 966-6547. Fax: (919) 966-5640. E-mail: nicholas{at}med.unc.edu.

Antimicrobial Agents and Chemotherapy, March 2002, p. 769-777, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.769-777.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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