Abstract
The branched-chain amino acids (BCAAs [Ile, Leu, and Val]) represent important nutrients in bacterial physiology, with roles that range from supporting protein synthesis to signaling and fine-tuning the adaptation to amino acid starvation. In some pathogenic bacteria, the adaptation to amino acid starvation includes induction of virulence gene expression: thus, BCAAs support not only proliferation during infection, but also the evasion of host defenses. A body of research has accumulated over the years to describe the multifaceted physiological roles of BCAAs and the mechanisms bacteria use to maintain their intracellular levels. More recent studies have focused on understanding how fluctuations in their intracellular levels impact global regulatory pathways that coordinate the adaptation to nutrient limitation, especially in pathogenic bacteria. In this minireview, we discuss how these studies have refined the individual roles of BCAAs, shed light on how BCAA auxotrophy might promote higher sensitivity to exogenous BCAA levels, and revealed pathogen-specific responses to BCAA deprivation. These advancements improve our understanding of how bacteria meet their nutritional requirements for growth while simultaneously remaining responsive to changes in environmental nutrient availability to promote their survival in a range of environments.
Highlights
The branched-chain amino acids (BCAAs [Ile, Leu, and Val]) represent important nutrients in bacterial physiology, with roles that range from supporting protein synthesis to signaling and fine-tuning the adaptation to amino acid starvation
That two recent studies have uncovered that both pathogens tightly regulate BCAA biosynthesis via a shared mechanism resulting in a BCAA “auxotrophy” phenotype, which might allow them to increase their capacity to respond to a wider range of BCAA levels to reduce the likelihood of untimely virulence determinant expression [69, 76]
DIRECTIONS Recent advancements in the area of BCAA metabolism have identified the importance of BCAA acquisition and synthesis for pathogen growth in vivo and have revealed that a pathogen’s preferred strategy reflects its unique physiological needs and host tissue preferences
Summary
Bacteria sense a variety of physical and chemical signals in their environment and use this information to coordinate an adaptive response that promotes their growth and survival. Several transcriptional regulators are positioned at the intersection of metabolism and pathogenesis, such as CcpA (responds to a preferred carbon source), CodY (responds to GTP and branched-chain amino acids [BCAAs]), and RpiR (responds to pentose phosphate pathway intermediates) [1, 2] The relevance of such regulators to gross bacterial physiology is typically evidenced by mutating the regulator and measuring transcriptional changes to identify shifts in metabolism that presumably allow the pathogen to adapt to restriction of a given nutritional signal. BCAAs AS INDICATORS OF CELLULAR METABOLIC STATUS In addition to their physiological roles, the BCAAs are effectors of the global transcriptional regulators leucine-responsive regulatory protein (Lrp) in Gram-negative bacteria and CodY in Gram-positive bacteria [23, 24] These global regulators coordinate the response to nutrient availability and regulate metabolic reprogramming to sustain growth upon nutrient exhaustion, as exemplified by the characteristic metabolic shift to stationary phase under laboratory growth conditions (Fig. 2). S. aureus is able to grow in the absence of Val only upon selection
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