JAC Advance Access published online on March 15, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm058
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AdeABC multidrug efflux pump is associated with decreased susceptibility to tigecycline in Acinetobacter calcoaceticus–Acinetobacter baumannii complex
Department of Infectious Disease, Wyeth Research, Pearl River, NY 10965, USA
Received 25 October 2006; returned 5 December 2006; revised 21 December 2006; accepted 5 February 2007
* Corresponding author. Tel: +1-845-602-4592; Fax: +1-845-602-5671; E-mail: ruzina{at}wyeth.com
Objectives: To investigate the role of the AdeABC multidrug efflux pump in the decreased susceptibility of clinical isolates of Acinetobacter calcoaceticus–Acinetobacter baumannii complex to tigecycline.
Methods: Gene expression was analysed by Taqman RT-PCR. A single cross-over achieved insertional inactivation of the adeB gene with a suicide plasmid construct carrying an adeB fragment obtained by PCR. Analysis of the adeRS locus was performed by PCR and sequencing. Ribotyping was performed with the RiboPrinter system. MICs were determined by Etest.
Results: Expression analysis revealed constitutive overexpression of adeABC in less-susceptible clinical isolates G5139 and G5140 (tigecycline MIC = 4 mg/L) when compared with the isogenic clinical isolates G4904 and G5141 (MIC = 1.5 mg/L). Insertional mutants GC7945 (adeB knockout in G5139) and GC7951 (adeB knockout in G5140) were obtained, which resulted in tigecycline MICs of 0.5 mg/L. As reported previously, the expression of adeABC is regulated by the two-component signalling system encoded by the adeR and adeS genes. PCR and sequencing analyses revealed an insertion of an ISABA-1 element in the adeS gene of G5139 and G5140.
Conclusions: The results of this study suggest that decreased susceptibility to tigecycline in the A. calcoaceticus–A. baumannii complex is associated with the overexpression of the AdeABC multidrug efflux pump.
Key Words: Acinetobacter , antibiotic resistance , efflux pump expression , RT-PCR , gene inactivation
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