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Antimicrob. Agents Chemother. doi:10.1128/AAC.01071-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Resistance to Glycopeptide Antibiotics in the Teicoplanin Producer is Mediated by van-Gene Homologue Expression Directing the Synthesis of a Modified Cell Wall Peptidoglycan

Vicuron Pharmaceuticals, Via R. Lepetit, 34, 21040, Gerenzano (Varese) Italy, Dipartimento di Biologia, Università degli Studi di Roma Tre, Viale Marconi 446, 00164 Roma, Italy, Dipartimento di Biotecnologie e Scienze Molecolari, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese Italy

^* To whom correspondence should be addressed. Email: fbeltrametti{at}vicuron.it.

	Abstract

Glycopeptide resistance has been studied in detail in enterococci and staphylococci. In these microorganisms, high-level resistance is achieved by replacing the C-terminal D-alanyl-D -alanine of the nascent peptidoglycan with D-alanyl-D -lactate or D-alanyl-D -serine, thus reducing glycopeptide affinity for cell wall targets. Reorganization of cell wall is directed by the expression of the van gene clusters. The identification of van gene homologues in the genomes of several glycopeptide-producing actinomycetes, suggests involvement of a similar self-resistance mechanism to avoid suicide. This report describes a comprehensive study of self-resistance in Actinoplanes teichomyceticus ATCC 31121, the producer of the clinically relevant glycopeptide teicoplanin. A. teichomyceticus ATCC 31121 showed a MIC of teicoplanin of 25 µg/ml and of vancomycin of 90 µg/ml during vegetative growth. The vanH_at, A_at and X_at genes were found organized in an operon, whose transcription was constitutive. Analysis of the UDP-linked peptidoglycan precursors revealed the presence of UDP-glycomuramyl pentadepsipeptide terminating in D-alanyl-D -lactate. No trace of precursors ending in D-alanyl-D -alanine was detected. Thus the van gene complex was transcribed and expressed in the genetic background of A. teichomyceticus, conferring resistance to vancomycin and teicoplanin through the modification of cell wall biosynthesis. During teicoplanin production (maximum productivity of 70-80 µg/ml), MIC of teicoplanin remained in the range 25-35 µg/ml. Teicoplanin producing cells were found tolerant to high concentrations of exogenously added glycopeptides, which resulted not bactericidal even at 5000 µg/ml.

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