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Antimicrobial Agents and Chemotherapy, September 2002, p. 2914-2919, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2914-2919.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Characterization of Sparsomycin Resistance in Streptomyces sparsogenes

E. Lázaro,,{dagger} E. Sanz, M. Remacha, and J. P. G. Ballesta*

Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, Canto Blanco, 28049 Madrid, Spain

Received 11 December 2001/ Returned for modification 4 March 2002/ Accepted 14 June 2002

The antitumor antibiotic sparsomycin, produced by Streptomyces sparsogenes, is a universal translation inhibitor that blocks the peptide bond formation in ribosomes from all species. Sparsomycin-resistant strains were selected by transforming the sensitive Streptomyces lividans with an S. sparsogenes library. Resistance was linked to the presence of a plasmid containing an S. sparsogenes 5.9-kbp DNA insert. A restriction analysis of the insert traced down the resistance to a 3.6-kbp DNA fragment, which was sequenced. The analysis of the fragment nucleotide sequence together with the previous restriction data associate the resistance to srd, an open reading frame of 1,800 nucleotides. Ribosomes from S. sparsogenes and the S. lividans-resistant strains are equally sensitive to the inhibitor and bind the drug with similar affinity. Moreover, the drug was not modified by the resistant strains. However, resistant cells accumulated less antibiotic than the sensitive ones. In addition, membrane fractions from the resistant strains showed a higher capacity for binding the drug. The results indicate that resistance in the producer strain is not connected to either ribosome modification or drug inactivation, but it might be related to an alteration in the sparsomycin permeability barrier.

* Corresponding author. Mailing address: Centro de Biología Molecular, Canto Blanco, 28049 Madrid, Spain. Phone: 34 913975076. Fax: 34 913974799. E-mail: jpgballesta{at}cbm.uam.es.

{dagger} Present address: Centro de Astrobiología (CSIC-INTA), Carretera de Ajalvir, Torrejón de Ardoz, Madrid, Spain.

Antimicrobial Agents and Chemotherapy, September 2002, p. 2914-2919, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2914-2919.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.





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