Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum

Radmacher E, Stansen KC, Besra GS, Alderwick LJ, Maughan WN, Hollweg G, Sahm H, Wendisch VF, Eggeling L (2005)
Microbiology-Sgm 151(5): 1359-1368.

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Abstract
Corynebacterium glutamicum is used for the large-scale production of L-glutamate, but the efflux of this amino acid is poorly understood. This study shows that addition of ethambutol (EMB) to growing cultures of C. glutamicum causes L-glutamate efflux at rates of up to 15 nmol min(-1) (mg dry wt)(-1), whereas in the absence of EMB, no efflux occurs. EMB is used for the treatment of Mycobacterium tuberculosis, and at a molecular level it targets a series of arabinosyltransferases (EmbCAB). The single arabinosyltransferase-encoding emb gene of C. glutamicum was placed under the control of a Tet repressor (TetR). Experiments with this strain, as well as with an emb-overexpressing strain, coupled with biochemical analyses showed that: (i) emb expression was correlated with L-glutamate efflux, (ii) emb overexpression increased EMB resistance, (iii) EMB caused less arabinan deposition in cell wall arabinogalactan, and (iv) EMB caused a reduced content of cell-wall-bound mycolic acids. Thus EMB addition resulted in a marked disordering of the cell envelope, which was also discernible by examining cellular morphology. In order to further characterize the cellular response to EMB addition, genome-wide expression profiling was performed using DNA microarrays. This identified 76 differentially expressed genes, with 18 of them upregulated more than eightfold. Among these were the cell-wall-related genes ftsE and mepA (encoding a secreted metalloprotease); however, genes of central metabolism were largely absent. Given that an altered lipid composition of the plasma membrane of C. glutamicum can result in L-glutamate efflux, we speculate that major structural alterations of the cell envelope are transmitted to the membrane, which in turn activates an export system, perhaps via increased membrane tension.
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Radmacher E, Stansen KC, Besra GS, et al. Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum. Microbiology-Sgm. 2005;151(5):1359-1368.
Radmacher, E., Stansen, K. C., Besra, G. S., Alderwick, L. J., Maughan, W. N., Hollweg, G., Sahm, H., et al. (2005). Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum. Microbiology-Sgm, 151(5), 1359-1368.
Radmacher, E., Stansen, K. C., Besra, G. S., Alderwick, L. J., Maughan, W. N., Hollweg, G., Sahm, H., Wendisch, V. F., and Eggeling, L. (2005). Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum. Microbiology-Sgm 151, 1359-1368.
Radmacher, E., et al., 2005. Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum. Microbiology-Sgm, 151(5), p 1359-1368.
E. Radmacher, et al., “Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum”, Microbiology-Sgm, vol. 151, 2005, pp. 1359-1368.
Radmacher, E., Stansen, K.C., Besra, G.S., Alderwick, L.J., Maughan, W.N., Hollweg, G., Sahm, H., Wendisch, V.F., Eggeling, L.: Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum. Microbiology-Sgm. 151, 1359-1368 (2005).
Radmacher, E., Stansen, K. C., Besra, G. S., Alderwick, L. J., Maughan, W. N., Hollweg, G., Sahm, H., Wendisch, Volker F., and Eggeling, L. “Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum”. Microbiology-Sgm 151.5 (2005): 1359-1368.
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