Applied Microbiology and Biotechnology

, Volume 97, Issue 16, pp 7151–7163

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

  • Kevin McClay
  • Baojie Wan
  • Yuehong Wang
  • Sanghyun Cho
  • Jerry Yu
  • Bernard Santarsiero
  • Shahila Mehboob
  • Michael Johnson
  • Scott Franzblau
  • Robert Steffan
Biotechnological products and process engineering

DOI: 10.1007/s00253-013-5012-9

Cite this article as:
McClay, K., Wan, B., Wang, Y. et al. Appl Microbiol Biotechnol (2013) 97: 7151. doi:10.1007/s00253-013-5012-9

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.

Keywords

TBTuberculosisCombinatorial biocatalysisAntibioticIndoleOxygenase

Supplementary material

253_2013_5012_MOESM1_ESM.pdf (449 kb)
ESM 1(PDF 448 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Kevin McClay
    • 1
  • Baojie Wan
    • 2
  • Yuehong Wang
    • 2
  • Sanghyun Cho
    • 2
  • Jerry Yu
    • 3
  • Bernard Santarsiero
    • 3
  • Shahila Mehboob
    • 3
  • Michael Johnson
    • 3
  • Scott Franzblau
    • 2
  • Robert Steffan
    • 1
  1. 1.CB&ILawrencevilleUSA
  2. 2.Institute for Tuberculosis Research, College of PharmacyUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Center for Pharmaceutical BiotechnologyUniversity of Illinois at ChicagoChicagoUSA