Staphylococcus aureus Transcriptome Data and Metabolic Modelling Investigate the Interplay of Ser/Thr Kinase PknB, Its Phosphatase Stp, the glmR/yvcK Regulon and the cdaA Operon for Metabolic Adaptation

Abstract

Serine/threonine kinase PknB and its corresponding phosphatase Stp are important regulators of many cell functions in the pathogen S. aureus. Genome-scale gene expression data of S. aureus strain NewHG (sigB+) elucidated their effect on physiological functions. Moreover, metabolic modelling from these data inferred metabolic adaptations. We compared wild-type to deletion strains lacking pknB, stp or both. Ser/Thr phosphorylation of target proteins by PknB switched amino acid catabolism off and gluconeogenesis on to provide the cell with sufficient components. We revealed a significant impact of PknB and Stp on peptidoglycan, nucleotide and aromatic amino acid synthesis, as well as catabolism involving aspartate transaminase. Moreover, pyrimidine synthesis was dramatically impaired by stp deletion but only slightly by functional loss of PknB. In double knockouts, higher activity concerned genes involved in peptidoglycan, purine and aromatic amino acid synthesis from glucose but lower activity of pyrimidine synthesis from glucose compared to the wild type. A second transcriptome dataset from S. aureus NCTC 8325 (sigB-) validated the predictions. For this metabolic adaptation, PknB was found to interact with CdaA and the yvcK/glmR regulon. The involved GlmR structure and the GlmS riboswitch were modelled. Furthermore, PknB phosphorylation lowered the expression of many virulence factors, and the study shed light on S. aureus infection processes.

Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes

“…This connection is strengthened by results reporting that Stk1 stimulates expression of glmS. 64 Another example of a loratadine-modulated DEG on its own having widespread impact cell-wide is the biofilm regulator icaR. This gene product represses the translation of the icaABDC operon.…”

Preliminary X-ray diffraction and ligand-binding analyses of the N-terminal domain of hypothetical protein Rv1421 from Mycobacterium tuberculosis H37Rv

“…M. tuberculosis, like B. subtilis, possesses two conserved consecutive genes, Rv1421 and Rv1422 [which correspond to YvcJ and GlmR (formerly YvcK), respectively, in B. subtilis] (Foulquier et al, 2020;Jeong & Lee, 2020;Jeong et al, 2023), that are involved in regulating the activity of GlmS, which catalyzes the production of UDP-GlcNAc as a cytoplasmic precursor of peptidoglycan (Sperber & Herman, 2017;Foulquier et al, 2020, Liang et al, 2021. However, compared with BsYvcJ, the sequence identity of MtRv1421 is approximately 42%.…”