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CodY, a nutritional regulator highly conserved in low G+C Gram-positive bacteria, is essential in  Streptococcus pneumoniae  (the pneumococcus). A published  codY  mutant possessed suppressing mutations inactivating the  fatC  and  amiC  genes, respectively belonging to iron (Fat/Fec) and oligopeptide (Ami) ABC permease operons, which are directly repressed by CodY. Here we analyzed two additional published  codY  mutants to further explore the essentiality of CodY. We show that one, in which the regulator of glutamine/glutamate metabolism  glnR  had been inactivated by design, had only a suppressor in  fecE  (a gene in the  fat/fec  operon), while the other possessed both  fecE  and  amiC  mutations. Independent isolation of three different  fat/fec  suppressors thus establishes that reduction of iron import is crucial for survival without CodY. We refer to these as primary suppressors, while inactivation of  ami , which is not essential for survival of  codY  mutants and acquired after initial  fat/fec  inactivation, can be regarded as a secondary suppressor. The availability of  codY   -   ami   +  cells allowed us to establish that CodY activates competence for genetic transformation indirectly, presumably by repressing  ami  which is known to antagonize competence. The  glnR codY fecE  mutant was then found to be only partially viable on solid medium and hypersensitive to peptidoglycan (PG) targeting agents such as the antibiotic cefotaxime and the muramidase lysozyme. While analysis of PG and teichoic acid composition uncovered no alteration in the  glnR codY fecE  mutant compared to wildtype, electron microscopy revealed altered ultrastructure of the cell wall in the mutant, establishing that co-inactivation of GlnR and CodY regulators impacts pneumococcal cell wall physiology. In light of rising levels of resistance to PG-targeting antibiotics of natural pneumococcal isolates, GlnR and CodY constitute potential alternative therapeutic targets to combat this debilitating pathogen, as co-inactivation of these regulators renders pneumococci sensitive to iron and PG-targeting agents.

Co-Inactivation of GlnR and CodY Regulators Impacts Pneumococcal Cell Wall Physiology