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

• DOI: 10.1093/jb/mvp096
• Publication Date: 2009-06-30T00:13:57Z
• Authors: T. Mogi; Y. Murase; M. Mori; K. Shiomi; S. Omura; M. P. Paranagama; K. Kita
• Keywords: Mycobacterium smegmatis; Malate dehydrogenase; Polymyxin B; Polymyxin

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