| Capsular polysaccharide (CPS) produced by pathogenic bacteria, including Streptococcus pneumoniae, is a key virulence determinant for bacterial survival in mammalian hosts. However, the specificsof CPS biosynthesis regulation remainunclear. Pneumococcus must modulate CPS thickness among various host niches during disease progression. We postulated that transition metalavailability may influence CPS production. Here, we show that pneumococcal cells incapable of exporting manganese (Mn)produce up to ≈30% thicker capsules, while Mn-limitation leads to ≈50% reduced CPS. The Mn-utilizing pair, CpsDand CpsB, are thought to regulate CPS production. Instead, we find that Mn/Zn ratios influence CPS production via Mn-dependent activation of the phosphoglucomutase Pgm, anenzyme that functions at the point between glycolysis and the CPS biosynthetic pathway. These data reveal a direct role for Mn homeostasis in the regulation of CPS biogenesis via Mn activation of Pgmand a link between this homeostasis and bacterial virulence.Key Words:Streptococcus pneumoniae, capsular polysaccharide, manganese homeostasis, tyrosine phosphatase, phosphoglucomutase |