[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
Kelly Flentie, Gregory A. Harrison, Hasan Tükenmez, Jonathan Livny, James A. D. Good, Souvik Sarkar, Dennis X. Zhu, Rachel L. Kinsella, Leslie A. Weiss, Samantha D. Solomon, Miranda E. Schene, Mette R. Hansen, Andrew G. Cairns, Martina Kulén, Torbjörn Wixe, Anders E. G. Lindgren, Erik Chorell, Christoffer Bengtsson, K. Syam Krishnan, Scott J. Hultgren, Christer Larsson, Fredrik Almqvist, and Christina L. Stallings
PNAS first published May 6, 2019 / DOI: https://doi.org/10.1073/pnas.1818009116
Edited by Caroline S. Harwood, University of Washington, Seattle, WA, and approved April 5, 2019 (received for review October 22, 2018)
Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis (TB), which kills more people than any other infection. The emergence of drug-resistant Mtb strains has exacerbated this already alarming epidemic. We have identified a small molecule, C10, that potentiates the activity of the frontline antibiotic isoniazid (INH) and prevents the selection for INH-resistant mutants. We find that C10 can even reverse INH resistance in Mtb. Therefore, our study reveals vulnerabilities that can be exploited to reverse INH resistance in Mtb.
Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.
Mycobacterium tuberculosis – drug tolerance – antibiotic resistance – isoniazid – respiration
1 K.F. and G.A.H. contributed equally to this work.
2 To whom correspondence may be addressed. Email: email@example.com or firstname.lastname@example.org.
Author contributions: K.F., G.A.H., and C.L.S. designed research; K.F., G.A.H., H.T., J.L., D.X.Z., R.L.K., L.A.W., S.D.S., M.E.S., and C.L. performed research; J.L., J.A.D.G., S.S., M.R.H., A.G.C., M.K., T.W., A.E.G.L., E.C., C.B., K.S.K., and F.A. contributed new reagents/analytic tools; K.F., G.A.H., H.T., J.L., J.A.D.G., D.X.Z., R.L.K., L.A.W., S.D.S., M.E.S., S.J.H., C.L., F.A., and C.L.S. analyzed data; and K.F., G.A.H., and C.L.S. wrote the paper.
Conflict of interest statement: C.L.S., S.J.H., and F.A. have ownership interests in Quretech Bio AB, which licenses C10.
This article is a PNAS Direct Submission.
Data Deposition: The RNA-sequencing data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE129835).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818009116/-/DCSupplemental.
Published under the PNAS license.
Keywords: Tuberculosis; Antibiotics; Drugs Resistance; Isoniazid.