Resistance to Enediyne Antitumor Antibiotics by Sequestration

Chin-Yuan Chang, Xiaohui Yan, Ivana Crnovcic, Thibault Annaval, Changsoo Chang, Boguslaw Nocek, Jeffrey D. Rudolf, Dong Yang, Hindra, Gyorgy Babnigg, Andrzej Joachimiak, George N. Phillips, Ben Shen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the enediyne producers—apoproteins for the nine-membered enediynes and self-sacrifice proteins for the ten-membered enediyne calicheamicin. Here we show that: (1) tnmS1, tnmS2, and tnmS3 encode tiancimycin (TNM) resistance in its producer Streptomyces sp. CB03234, (2) tnmS1, tnmS2, and tnmS3 homologs are found in all anthraquinone-fused enediyne producers, (3) TnmS1, TnmS2, and TnmS3 share a similar β barrel-like structure, bind TNMs with nanomolar KD values, and confer resistance by sequestration, and (4) TnmS1, TnmS2, and TnmS3 homologs are widespread in nature, including in the human microbiome. These findings unveil an unprecedented resistance mechanism for the enediynes. Mechanisms of self-resistance in producers serve as models to predict and combat future drug resistance in clinical settings. Enediyne-based chemotherapies should now consider the fact that the human microbiome harbors genes encoding enediyne resistance. TnmS1, TnmS2, and TnmS3 confer tiancimycin resistance by sequestration. Their homologs are found in all anthraquinone-fused enediyne producers and are widespread in nature, including in the human microbiome. These findings unveil an unprecedented resistance mechanism for the enediynes and should be considered in future efforts to develop enediyne-based chemotherapies.

Original languageEnglish
Pages (from-to)1075-1085.e4
JournalCell Chemical Biology
Volume25
Issue number9
DOIs
StatePublished - 20 Sep 2018

Keywords

  • anthraquinone-fused enediyne
  • antibody-drug conjugate
  • anticancer drug
  • biosynthesis
  • enediyne
  • resistance
  • sequence similarity network
  • sequestration
  • the human microbiome
  • tiancimycin

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