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l-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species

  • Junfeng Zhen
  • Shuangquan Yan
  • Yuzhu Li
  • Cao Ruan
  • Yue Li
  • Xue Li
  • Xiaokang Zhao
  • Xi Lv
  • Yan Ge
  • Ulrich Aymard Ekomi Moure
  • Jianping XieEmail author
Applied genetics and molecular biotechnology

Abstract

Tuberculosis caused by Mycobacterium tuberculosis remains a major global health concern; M. tuberculosis drug resistance and persistence further fueled the situation. Nutrient supportive therapy was intensively pursued to complement the conventional treatment, as well as their synergy with current antibiotics. To explore whether l-alanine can synergize with fluoroquinolones against M. tuberculosis, M. smegmatis was used as a surrogate in this study. We found that l-alanine can boost the bactericidal efficacy of fluoroquinolones, increasing the production of intracellular reactive oxygen species. This effect is very significant for persisters. Accelerated tricarboxylic acid cycle and/or nucleotide metabolism were observed after the addition of l-alanine. M. smegmatis MSMEG2660 is a homolog of the alanine dehydrogenase (Rv2780, MSMEG2659) negative regulator Rv2779c and involved in the l-alanine potentiation of fluoroquinolone via funneling more alanine into tricarboxylic acid. Deletion mutant of the MSMEG2660 (∆Ms2660) became more susceptible, and more readily revived from persistence. We firstly found that l-alanine can synergize with fluoroquinolones against Mycobacterium, especially the persisters via promoting metabolism. This will inspire new avenue to eliminate Mycobacterium persisters.

Keywords

Persistence Alanine Fluoroquinolone Mycobacterium Reactive oxygen species 

Notes

Author contributions

Jianping Xie and Shuangquan Yan directed the study; Junfeng Zhen, Shuangquan Yan, and Jianping Xie designed the study; Junfeng Zhen, Yuzhu Li, Cao Ruan, and Xiaokang Zhao performed the experiments; Yue Li, Xue Li, Xi Lv, and Yan Ge prepared the materials and analyzed the date. Junfeng Zhen, Jianping Xie, and Moure U.A.E. wrote the manuscript. All authors read and approved the manuscript.

Funding information

This study was supported by National Natural Science Foundation (grant numbers 81871182, 81371851), National Key R&D Plan (2016YFC0502304), the Fundamental Research Funds for the Central Universities (grant numbers XDJK2017D101, XDJK2017D100, XDJK2017D099), and the Chongqing Municipal Education Commission for postgraduates innovation program, China (grant number CYB18076).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any other authors.

Supplementary material

253_2020_10358_MOESM1_ESM.lpdf (158 kb)
ESM 1 (LPDF 157 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Junfeng Zhen
    • 1
  • Shuangquan Yan
    • 1
  • Yuzhu Li
    • 1
  • Cao Ruan
    • 1
  • Yue Li
    • 1
  • Xue Li
    • 1
  • Xiaokang Zhao
    • 1
  • Xi Lv
    • 1
  • Yan Ge
    • 1
  • Ulrich Aymard Ekomi Moure
    • 1
  • Jianping Xie
    • 1
    Email author
  1. 1.Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life SciencesSouthwest UniversityChongqingChina

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