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JAC Advance Access originally published online on July 8, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(2):393-400; doi:10.1093/jac/dkh364
JAC vol.54 no.2 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

Inability of L22 ribosomal protein alteration to increase macrolide MICs in the absence of efflux mechanism in Haemophilus influenzae HMC-S

Mihaela Peric1,{dagger}, Bülent Bozdogan1,*, Chad Galderisi1, Dan Krissinger2, Terry Rager2 and Peter C. Appelbaum1

1 Department of Pathology, Hershey Medical Center, Mail code H083, 500 University Dr., Hershey, PA 17033; 2 Functional Genomic Core Hershey Medical Center, Hershey, PA 17033, USA

* Corresponding author. Tel: +1-717-531-3910; Fax: +1-717-531-7953; Email: bozdogan-b{at}psu.edu

Background: Haemophilus influenzae HMC-C with high-level macrolide resistance after multi-step selection by clarithromycin reverted spontaneously and became hypersusceptible to macrolides.

Objective: Determination of macrolide resistance mechanism(s) in hypersusceptible and hyperresistant strains.

Methods: The presence of macrolide efflux in the strains was studied by radioactive erythromycin accumulation. Ribosomal mutations were investigated by sequencing. The possible role of acrAB clusters in macrolide resistance was studied by sequencing and expression analysis.

Results: The parent strain had no ribosomal alteration, but both high-level resistant and hypersusceptible strains had R88P mutations in ribosomal protein L22. Radioactive macrolide accumulation studies pointed to the presence of macrolide efflux in the high-level resistant and parent strains, but not in the hypersusceptible derivative. Transformation of hypersusceptible strains using total DNA from the parent strain restored the macrolide efflux system in the hypersusceptible strain, which was confirmed by MIC levels and radioactive erythromycin accumulation similar to that of the mutant resistant strain. Analysis of sequence and transcription of acrAB gene clusters showed no significant differences between resistant and hypersusceptible derivatives.

Conclusion: Mutation in ribosomal protein L22 alone does not confer high-level macrolide resistance unless efflux is present.

Keywords: macrolide resistance , H. influenzae , macrolide efflux , ribosomal mutations


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