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Antimicrobial Agents and Chemotherapy, August 2007, p. 2784-2792, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00412-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Target Gene Sequencing To Characterize the Penicillin G Susceptibility of Neisseria meningitidis

Neisseria Unit, Institut Pasteur, Paris, France,¹ Reference Laboratory for Neisserias, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, Madrid, Spain,² Epidemiology and Molecular Biology Unit and Irish Meningococcal and Meningitis Reference Laboratory, The Children's University Hospital, Dublin, Ireland,³ National Reference Centre for Neisseria meningitidis, Bacteriology division, Scientific Institute of Public Health, Brussels, Belgium,⁴ University Hospital for Infectious Diseases, Zagreb, Croatia,⁵ Neisseria and Streptococcus Reference laboratory, Statens Serum Institut, Copenhagen, Denmark,⁶ Scottish Meningococcus and Pneumococcus Reference Laboratory, Stobhill Hospital, Glasgow, United Kingdom,⁷ Department of Infectious, Parasitic, and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy,⁸ Institute for Hygiene and Microbiology, National Reference Center for Meningococci, University of Würzburg, Würzburg, Germany,⁹ National Reference Centre for Meningococci, Austrian Agency for Health and Food Safety, Graz, Austria,¹⁰ Peter Medawar Building and Department of Zoology, University of Oxford, Oxford, United Kingdom,¹¹ National Reference Centre for Bacterial Meningitis, National Medicine Institute, Warsaw, Poland,¹² Hôpital d'Enfants, Tunis, Tunisia,¹³ National Meningitis Reference Laboratory, National School of Public Health, Athens, Greece,¹⁴ National Reference Laboratory for Meningococcal Infections, National Institute of Public Health, Prague, Czech Republic,¹⁵ Cantacusino Institute, Bucharest, Romania,¹⁶ Institute of Public Health, Communicable Diseases Centre, Ljubljana, Slovenia,¹⁷ National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden,¹⁸

Received 26 March 2007/ Returned for modification 19 April 2007/ Accepted 11 May 2007

Clinical isolates of Neisseria meningitidis with reduced susceptibility to penicillin G (intermediate isolates, Pen^I) harbor alterations in the penA gene encoding the penicillin binding protein 2 (PBP2). A 402-bp DNA fragment in the 3' half of penA was sequenced from a collection of 1,670 meningococcal clinical isolates from 22 countries that spanned 60 years. Phenotyping, genotyping, and the determination of MICs of penicillin G were also performed. A total of 139 different penA alleles were detected with 38 alleles that were highly related, clustered together in maximum-likelihood analysis and corresponded to the penicillin G-susceptible isolates. The remaining 101 penA alleles were highly diverse, corresponded to different genotypes or phenotypes, and accounted for 38% of isolates, but no clonal expansion was detected. Analysis of the altered alleles that were represented by at least five isolates showed high correlation with the Pen^I phenotype. The deduced amino acid sequence of the corresponding PBP2 comprised five amino acid residues that were always altered. This correlation was not complete for rare alleles, suggesting that other mechanisms may also be involved in conferring reduced susceptibility to penicillin. Evidence of mosaic structures through events of interspecies recombination was also detected in altered alleles. A new website was created based on the data from this work (http://neisseria.org/nm/typing/penA). These data argue for the use of penA sequencing to identify isolates with reduced susceptibility to penicillin G and as a tool to improve typing of meningococcal isolates, as well as to analyze DNA exchange among Neisseria species.

Published ahead of print on 21 May 2007.

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