Identification of a chemical that inhibits the mycobacterial UvrABC complex in nucleotide excision repair

Nayef Mazloum, Melanie A. Stegman, Deborah L. Croteau, Bennett Van Houten, Nyoun Soo Kwon, Yan Ling, Caitlyn Dickinson, Aditya Venugopal, Mohammad Atif Towheed, Carl Nathan

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Abstract

Bacterial DNA can be damaged by reactive nitrogen and oxygen intermediates (RNI and ROI) generated by host immunity, as well as by antibiotics that trigger bacterial production of ROI. Thus a pathogens ability to repair its DNA may be important for persistent infection. A prominent role for nucleotide excision repair (NER) in disease caused by Mycobacterium tuberculosis (Mtb) was suggested by attenuation of uvrB-deficient Mtb in mice. However, it was unknown if Mtbs Uvr proteins could execute NER. Here we report that recombinant UvrA, UvrB, and UvrC from Mtb collectively bound and cleaved plasmid DNA exposed to ultraviolet (UV) irradiation or peroxynitrite. We used the DNA incision assay to test the mechanism of action of compounds identified in a high-throughput screen for their ability to delay recovery of M. smegmatis from UV irradiation. 2-(5-Amino-1,3,4-thiadiazol-2-ylbenzo[f]chromen-3-one) (ATBC) but not several closely related compounds inhibited cleavage of damaged DNA by UvrA, UvrB, and UvrC without intercalating in DNA and impaired recovery of M. smegmatis from UV irradiation. ATBC did not affect bacterial growth in the absence of UV exposure, nor did it exacerbate the growth defect of UV-irradiated mycobacteria that lacked uvrB. Thus, ATBC appears to be a cell-penetrant, selective inhibitor of mycobacterial NER. Chemical inhibitors of NER may facilitate studies of the role of NER in prokaryotic pathobiology.

Original languageEnglish
Pages (from-to)1329-1335
Number of pages7
JournalBiochemistry
Volume50
Issue number8
DOIs
Publication statusPublished - 1 Mar 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Mazloum, N., Stegman, M. A., Croteau, D. L., Van Houten, B., Kwon, N. S., Ling, Y., Dickinson, C., Venugopal, A., Towheed, M. A., & Nathan, C. (2011). Identification of a chemical that inhibits the mycobacterial UvrABC complex in nucleotide excision repair. Biochemistry, 50(8), 1329-1335. https://doi.org/10.1021/bi101674c