Identification of novel inhibitors of phospho-MurNAc-pentapeptide translocase MraY from library screening: Isoquinoline alkaloid michellamine B and xanthene dye phloxine B |
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| Institution: | 1. P.G. Department of Chemistry, Karnatak University, Dharwad 580003, Karnataka, India;2. Department of Chemistry, K.L.S. Gogte Institute of Technology, Belgaum 590008, Karnataka, India;3. Department of Chemistry, V.D.R. Institute of Technology, Haliyal 581329, Karnataka, India;4. Department of Chemistry, C.M.R. Institute of Technology, Bangalore 560037, Karnataka, India;5. Department of Chemistry, Shri Sharanabasaveshwar College of Science, Gulbarga 585102, Karnataka, India;1. Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences (INMAS), New Delhi 110054, India;2. Department of Biotechnology, Jamia Hamdard, New Delhi 110062, India;3. Office of DG (LS), Defence Research and Development Organisation, DRDO Bhawan, New Delhi, India;1. Department of Chemical Engineering, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei Province 066004, China;2. MPC Technologies, Hamilton, Ontario, Canada L8S 3H4 |
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| Abstract: | The National Cancer Institute (NCI) Diversity Set was screened for potential inhibitors of phospho-MurNAc-pentapeptide translocase MraY from Escherichia coli using a primary fluorescence enhancement assay, followed by a secondary radiochemical assay. One new MraY inhibitor was identified from this screen, a naphthylisoquinoline alkaloid michellamine B, which inhibited E. coli MraY (IC50 456 μM) and Bacillus subtilis MraY (IC50 386 μM), and which showed antimicrobial activity against B. subtilis (MIC 16 μg/mL). Following an earlier report of halogenated fluoresceins identified from a combined MraY/MurG screen, three halogenated fluoresceins were tested as inhibitors of E. coli MraY and E. coli MurG, and phloxine B was identified as an inhibitor of E. coli MraY (IC50 32 μM). Molecular docking of inhibitor structures against the structure of Aquifex aeolicus MraY indicates that phloxine B appears to bind to the Mg2+ cofactor in the enzyme active site, while michellamine B binds to a hydrophobic groove formed between transmembrane helices 5 and 9. |
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| Keywords: | Peptidoglycan biosynthesis Antibacterial Translocase MraY Enzyme inhibition Michellamine B |
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