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Journal of Bacteriology, May 2007, p. 3581-3590, Vol. 189, No. 9
0021-9193/07/$08.00+0     doi:10.1128/JB.01810-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Elongation Factor Tu3 (EF-Tu3) from the Kirromycin Producer Streptomyces ramocissimus Is Resistant to Three Classes of EF-Tu-Specific Inhibitors

Lian N. Olsthoorn-Tieleman,¹ Robert-Jan T. S. Palstra,^1, Gilles P. van Wezel,^1,2 Mervyn J. Bibb,² and Cornelis W. A. Pleij^1*

Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands,¹ Department of Genetics, John Innes Centre, Norwich NR4 7UH, United Kingdom²

Received 30 November 2006/ Accepted 21 February 2007

The antibiotic kirromycin inhibits prokaryotic protein synthesis by immobilizing elongation factor Tu (EF-Tu) on the elongating ribosome. Streptomyces ramocissimus, the producer of kirromycin, contains three tuf genes. While tuf1 and tuf2 encode kirromycin-sensitive EF-Tu species, the function of tuf3 is unknown. Here we demonstrate that EF-Tu3, in contrast to EF-Tu1 and EF-Tu2, is resistant to three classes of EF-Tu-targeted antibiotics: kirromycin, pulvomycin, and GE2270A. A mixture of EF-Tu1 and EF-Tu3 was sensitive to kirromycin and resistant to GE2270A, in agreement with the described modes of action of these antibiotics. Transcription of tuf3 was observed during exponential growth and ceased upon entry into stationary phase and therefore did not correlate with the appearance of kirromycin in stationary phase; thus, it is unlikely that EF-Tu3 functions as a resistant alternative for EF-Tu1. EF-Tu3 from Streptomyces coelicolor A3(2) was also resistant to kirromycin and GE2270A, suggesting that multiple antibiotic resistance is an intrinsic feature of EF-Tu3 species. The GE2270A-resistant character of EF-Tu3 demonstrated that this divergent elongation factor is capable of substituting for EF-Tu1 in vivo.

Published ahead of print on 2 March 2007.

Present address: Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.