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Journal of Biochemistry Advance Access originally published online on June 29, 2009
Journal of Biochemistry 2009 146(4):491-499; doi:10.1093/jb/mvp096
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© The Authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

Polymyxin B Identified as an Inhibitor of Alternative NADH Dehydrogenase and Malate: Quinone Oxidoreductase from the Gram-positive Bacterium Mycobacterium smegmatis

Tatsushi Mogi1,*, Yoshiro Murase2, Mihoko Mori3, Kazuro Shiomi3, Satoshi Omura3, Madhavi P. Paranagama1 and Kiyoshi Kita1

1Department of Biomedical Chemistry, Graduate School of Medicine, the University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033; 2Mycobacterium Reference Center, the Research Institute of Tuberculosis, Japan Anti-tuberculosis Association, Kiyose, Tokyo 204-8533; and 3Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Tokyo 108-8641, Japan

*To whom correspondence should be addressed. Tel: +81 3 5841 8202, Fax: +81 3 5841 3444, E-mail: tmogi{at}m.u-tokyo.ac.jp

Received May 11, 2009; Accepted June 10, 2009


  Abstract

Tuberculosis is the leading cause of death due to a single infectious agent in the world and the emergence of multidrug-resistant strains prompted us to develop new drugs with novel targets and mechanism. Here, we screened a natural antibiotics library with Mycobacterium smegmatis membrane-bound dehydrogenases and identified polymyxin B (cationic decapeptide) and nanaomycin A (naphtoquinone derivative) as inhibitors of alternative NADH dehydrogenase [50% inhibitory concentration (IC50) values of 1.6 and 31 µg/ml, respectively] and malate: quinone oxidoreductase (IC50 values of 4.2 and 49 µg/ml, respectively). Kinetic analysis on inhibition by polymyxin B showed that the primary site of action was the quinone-binding site. Because of the similarity in Km value for ubiquinone-1 and inhibitor sensitivity, we examined amino acid sequences of actinobacterial enzymes and found possible binding sites for L-malate and quinones. Proposed mechanisms of polymyxin B and nanaomycin A for the bacteriocidal activity were the destruction of bacterial membranes and production of reactive oxygen species, respectively, while this study revealed their inhibitory activity on bacterial membrane-bound dehydrogenases. Screening of the library with bacterial respiratory enzymes resulted in unprecedented findings, so we are hoping that continuing efforts could identify lead compounds for new drugs targeting to mycobacterial respiratory enzymes.

Key Words: Mycobacterium tuberculosis, NADH dehydrogenase, natural antibiotics, polymyxin B, respiratory chain

Abbreviations: IC50, the 50% inhibitory concentration; MDR, multidrug-resistant; MIC, minimum inhibitory concentration; MQO, malate: quinone oxidoreductase; NDH2, alternative NADH dehydrogenase; NQR, NADH: quinone reductase; Q1, ubiquinone-1; SDH, succinate dehydrogenase


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