Revisiting the β-lactams for tuberculosis therapy with a compound-compound synthetic lethality approach

Shiqi Xiao, Haidan Guo, Warren S. Weiner, Clinton Maddox, Chunhong Mao, Hendra Gunosewoyo, Shaaretha Pelly, E. Lucile White, Lynn Rasmussen, Frank J. Schoenen, Jeffrey Aubé, William R. Bishai, Shichun Lun

Research output: Contribution to journalArticle

Abstract

The suboptimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, the results of treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor were found to be encouraging in a case study of extensively drug-resistant tuberculosis (M. C. Payen, S. De Wit, C. Martin, R. Sergysels, et al., Int J Tuberc Lung Dis 16:558-560, 2012, https://doi.org/10.5588/ijtld.11.0414). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by noncanonical accessory proteins that are not considered the classic targets of β-lactams and that small-molecule inhibitors of those accessory targets might sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for the ability to sensitize M. tuberculosis to meropenem. We identified six hit compounds, belonging to either the N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mice. Structure-activity relationship studies of both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that oxidoreductases, MmpL family proteins, and a 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that were capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by β-lactam accessory proteins. β-Lactam compound-compound synthetic lethality may be an alternative approach for drug-resistant tuberculosis.

Original languageEnglish (US)
Article numbere0131919
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number11
DOIs
StatePublished - 2019

Keywords

  • High-throughput screen
  • Synthetic lethality
  • Tuberculosis
  • β-lactams

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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  • Cite this

    Xiao, S., Guo, H., Weiner, W. S., Maddox, C., Mao, C., Gunosewoyo, H., Pelly, S., Lucile White, E., Rasmussen, L., Schoenen, F. J., Aubé, J., Bishai, W. R., & Lun, S. (2019). Revisiting the β-lactams for tuberculosis therapy with a compound-compound synthetic lethality approach. Antimicrobial agents and chemotherapy, 63(11), [e0131919]. https://doi.org/10.1128/AAC.01319-19