The global nutritional regulator CodY is an essential protein in the human pathogen Streptococcus pneumoniae

Summary CodY is a global regulator highly conserved in low‐G+C Gram‐positive bacteria. It plays a key role in the adaptation of Bacillus subtilis to nutritional limitation through repression of a large gene set during exponential growth and relief of repression upon starvation. In several pathogenic bacteria, CodY regulates major virulence genes. Our interest in Streptococcus pneumoniae CodY originates from our observations that the oligopeptide permease Ami was involved in repression of competence for genetic transformation. We hypothesized that peptide uptake through Ami feeds amino acid pools, which are sensed by CodY to repress competence. As our initial attempts at inactivating codY failed, we launched an in‐depth analysis into the question of the essentiality of codY . We report that codY cannot be inactivated unless a complementing ectopic copy is present. We obtained genetic evidence that a recently published D39 codY knock‐out contains additional mutations allowing survival of codY mutant cells. Whole‐genome sequencing revealed mutations in fatC , which encodes a ferric iron permease, and amiC . This combination of mutations was confirmed to allow tolerance of codY inactivation. The amiC mutation is in itself sufficient to account for the strong derepression of competence development observed in D39 codY cells.