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Antimicrobial Agents and Chemotherapy, August 2005, p. 3129-3135, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3129-3135.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of the AcrAB-TolC Efflux Pump in Determining Susceptibility of Haemophilus influenzae to the Novel Peptide Deformylase Inhibitor LBM415

Charles R. Dean,1* Shubha Narayan,1 Denis M. Daigle,1 JoAnn L. Dzink-Fox,1 Xiaoling Puyang,1 Kathryn R. Bracken,1 Karl E. Dean,1 Beat Weidmann,1 Zhengyu Yuan,2 Rakesh Jain,2 and Neil S. Ryder1

Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139,1 Vicuron Pharmaceuticals, Fremont, California 945552

Received 26 October 2004/ Returned for modification 12 January 2005/ Accepted 5 May 2005

Haemophilus influenzae isolates vary widely in their susceptibilities to the peptide deformylase inhibitor LBM415 (MIC range, 0.06 to 32 µg/ml); however, on average, they are less susceptible than gram-positive organisms, such as Staphylococcus aureus and Streptococcus pneumoniae. Insertional inactivation of the H. influenzae acrB or tolC gene in strain NB65044 (Rd strain KW20) increased susceptibility to LBM415, confirming a role for the AcrAB-TolC pump in determining resistance. Consistent with this, sequencing of a PCR fragment generated with primers flanking the acrRA region from an LBM415-hypersusceptible H. influenzae clinical isolate revealed a genetic deletion of acrA. Inactivation of acrB or tolC in several clinical isolates with atypically reduced susceptibility to LBM415 (MIC of 16 µg/ml or greater) significantly increased susceptibility, confirming that the pump is also a determinant of decreased susceptibility in these clinical isolates. Examination of acrR, encoding the putative repressor of pump gene expression, from several of these strains revealed mutations introducing frameshifts, stop codons, and amino acid changes relative to the published sequence, suggesting that loss of pump repression leads to decreased susceptibility. Supporting this, NB65044 acrR mutants selected by exposure to LBM415 at 8 µg/ml had susceptibilities to LBM415 and other pump substrates comparable to the least sensitive clinical isolates and showed increased expression of pump genes.

* Corresponding author. Mailing address: Infectious Diseases, Novartis Institute for Biomedical Research, Inc., 100 Technology Square, Cambridge, MA 02139. Phone: (617) 871-3150. Fax: (617) 871-7047. E-mail: charlesr.dean{at}novartis.com.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3129-3135, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3129-3135.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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