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A novel combinatorial biocatalytic approach for producing antibacterial compounds effective against Mycobacterium tuberculosis (TB)

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Abstract

Two bacterial hosts expressing cloned aromatic oxygenases were used to catalyze the oxidation and polymerization of indole and related substrates, creating mixtures of indigoid compounds comprised of novel dimers and trimers. Crude extracts and purified compounds were tested for their ability to inhibit the growth of Gram-positive organisms, in general, and Mycobacterium tuberculosis (TB), in particular. Of the 74 compounds tested against M. tuberculosis, ~66 % had minimum inhibitory concentrations (MIC) of 5 μg/ml or less. The most effective antibiotic found was designated SAB-P1, a heterodimer of indole and anthranil, which had a MIC of 0.16 μg/ml, and did not inhibit kidney cells (IC50) at concentrations of >8 μg/ml. Combinatorial biocatalysis was used to create a series of halogenated derivatives of SAB-P1 with a wider therapeutic window. None of the derivatives had MIC values that were superior to SAB-P1, but some had a wider therapeutic window because of decreased kidney cell toxicity. Generally, the indigoid dimers that were effective against TB appeared to be specific for TB. Some of the trimers generated, however, had a broader spectrum of activity inhibiting not only TB (MIC = 1.1 μg/ml) but also the growth of Mycobacterium smegmatis MC2 155, Bacillus cereus, Enterococcus faecalis, Staphylococcus epidermidis, Bacillus subtilis 168, and Clostridium acetobutylicum. The structure of two of the novel dimers (SAB-C4 and SAB-P1) and a trimer (SAB-R1) were solved using X-ray crystallography.

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Acknowledgements

This work was supported, in part, by a grant from the Global TB Alliance. We would like to thank Christopher Cooper of the Global TB Alliance for his interest and guidance, Lining Cai of Biotranex for his assistance with LC/MS, and Larry Klein of UIC for his chemistry expertise.

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Authors and Affiliations

  1. CB&I, 17 Princess Rd., Lawrenceville, NJ, 08648, USA

    Kevin McClay & Robert Steffan

  2. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street, Chicago, IL, 60621-7231, USA

    Baojie Wan, Yuehong Wang, Sanghyun Cho & Scott Franzblau

  3. Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL, 60607, USA

    Jerry Yu, Bernard Santarsiero, Shahila Mehboob & Michael Johnson

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  1. Kevin McClay
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  2. Baojie Wan
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Correspondence to Kevin McClay.

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McClay, K., Wan, B., Wang, Y. et al. A novel combinatorial biocatalytic approach for producing antibacterial compounds effective against Mycobacterium tuberculosis (TB). Appl Microbiol Biotechnol 97, 7151–7163 (2013). https://doi.org/10.1007/s00253-013-5012-9

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