Dynamic exometabolome analysis reveals active metabolic pathways in non-replicating mycobacteria
In a collaborative effort of the Sauer and Zamboni labs at IMSB and the Berry Lab at NIH, Michael and his co-workers integrated dynamic changes in the secretion and uptake of metabolites with genome-scale metabolic network reconstructions and identified active metabolic routes necessary for mycobacteria survival under hypoxic conditions.
Abstract
An organism’s metabolic activity leaves an extracellular footprint and dynamic changes in this exometabolome inform about nutrient uptake, waste disposal and signaling activities. Using non-targeted mass spectrometry, we report exometabolome dynamics of hypoxia-induced, non-replicating mycobacteria that are thought to play a role in latent tuberculosis. Despite evidence of active metabolism, little is known about the mechanisms enabling obligate aerobic mycobacteria to cope with hypoxia, resulting in long-term survival and increased chemotherapeutic tolerance. The dynamics of 379 extracellular compounds of Mycobacterium smegmatis were deconvoluted with a genome-scale metabolic reaction-pair network to generate hypotheses about intracellular pathway usage. Time-resolved 13C-tracing and mutant experiments then demonstrated a crucial, energy-generating role of asparagine utilization and non-generic usage of the glyoxylate shunt for hypoxic fitness. Experiments with M. bovis and M. tuberculosis revealed the general relevance of asparagine fermentation and a variable contribution of the glyoxylate shunt to non-replicative, hypoxic survival between the three species.
Reference
Michael Zimmermann, Andreas Kühne, Helena I. Boshoff, Clifton E. Barry3rd, Nicola Zamboni, Uwe Sauer external pageDynamic exometabolome analysis reveals active metabolic pathways in non-replicating mycobacteriacall_made. (Environmental Microbiology, 2015 Sep 16)