Original Article

The Journal of Antibiotics (2010) 63, 23–28; doi:10.1038/ja.2009.116; published online 27 November 2009

Monooxygenation of rifampicin catalyzed by the rox gene product of Nocardia farcinica: structure elucidation, gene identification and role in drug resistance

Yasutaka Hoshino1, Shoko Fujii1,2, Hideki Shinonaga3, Koshi Arai3, Fumiko Saito1, Toshio Fukai4, Hiroyuki Satoh2, Yoshitsugu Miyazaki1 and Jun Ishikawa1

  1. 1Department of Bioactive Molecules, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
  2. 2Biology Major, Graduate School of Science, Toho University, Funabashi, Chiba, Japan
  3. 3Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
  4. 4Department of Health Pharmacy, Yokohama College of Pharmacy, Yokohama, Kanagawa, Japan

Correspondence: Dr J Ishikawa, Department of Bioactive Molecules, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku, Tokyo 162-8640, Japan. E-mail: jun@nih.go.jp

Received 28 May 2009; Revised 22 October 2009; Accepted 4 November 2009; Published online 27 November 2009.

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Abstract

We demonstrated that the rox gene of Nocardia farcinica encodes a rifampicin monooxygenase capable of converting rifampicin to a new compound 2′-N-hydroxy-4-oxo-rifampicin with a markedly lowered antibiotic activity. The deletion mutation (Δrox) of the rox gene gave no significant influence to the rifampicin resistance of N. farcinica. However, transformation with a plasmid containing an overexpressing the rox gene markedly raised the rifampicin resistance in the strain with the deletion mutation of the rpoB2 gene as the principal rifampicin resistance determinant. On the other hand, rifampicin was decolorized by the wild-type strain, whereas it remained intact when incubated with the Δrox strain. Based on these results, it will be conclusive that the rox gene is capable of initiating rifampicin degradation with a new metabolite formation at the first step and having a role as the secondary rifampicin resistance factor in N. farcinica.

Keywords:

drug resistance, monooxygenase, Nocardia farcinica, rifampicin, rox

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