l-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species
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.
KeywordsPersistence Alanine Fluoroquinolone Mycobacterium Reactive oxygen species
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.
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.
This article does not contain any studies with human participants or animals performed by any other authors.
- Aliasghar F, Omid S, Masoomeh S, Manijeh K (2015) Arginine adjunctive therapy in active tuberculosis. Tuberc Res Treat:1–5Google Scholar
- He F, Wu C, Li P, Li N, Zhang D, Zhu Q, Ren W, Peng Y (2018) Functions and signaling pathways of amino acids in intestinal inflammation. Biomed Res Int 2018(3):1–13Google Scholar
- Romanowski EG, Yates KA, Mah FS, Gordon YJ, Kowalski RP (2012) An antimicrobial peptide can enhance the activity of a fluoroquinolone in reducing colony counts of fluoroquinolone-resistant MRSA in the NZW rabbit keratitis model. Invest Ophthalmol Vis Sci 53(14):6257–6257Google Scholar