Synthesis of the capsular polysaccharide, a major virulence factor for many pathogenic bacteria, is required for bacterial survival within the infected host. In Streptococcus pneumoniae, Wze, an autophosphorylating tyrosine kinase, and Wzd, a membrane protein required for Wze autophosphorylation, co-localize at the division septum and guarantee the presence of capsule at this subcellular location. To determine how bacteria regulate capsule synthesis, we studied pneumococcal proteins that interact with Wzd and Wze using bacterial two hybrid assays and fluorescence microscopy. We found that Wzd interacts with Wzg, the putative ligase that attaches capsule to the bacterial cell wall, and recruits it to the septal area. This interaction required residue V56 of Wzd and both the transmembrane regions and DNA-PPF domain of Wzg. When compared to the wild type, Wzd null pneumococci lack capsule at midcell, bind the peptidoglycan hydrolase LytA better and are more susceptible to LytA-induced lysis, and are less virulent in a zebrafish embryo infection model. In this manuscript, we propose that the Wzd/Wze pair guarantees full encapsulation of pneumococcal bacteria by recruiting Wzg to the division septum, ensuring that capsule attachment is coordinated with peptidoglycan synthesis. Impairing the encapsulation process, at localized subcellular sites, may facilitate elimination of bacteria by strategies that target the pneumococcal peptidoglycan. Author summary: During their cell cycle, Gram-positive bacteria can be frequently found surrounded by a cellular envelope, which includes glycopolymers such as peptidoglycan, wall teichoic acids or capsular polysaccharides, whose composition is adjusted to the external insults they may find. The clarification of how bacteria tune synthesis of these three macromolecules, which act as defensive layers, ensuring efficient enclosing of bacteria and their protection from the surrounding medium, will permit a better understanding of how bacteria propagate and may pave the way to the intelligent design of anti-infective strategies. In this manuscript, we have determined how Wzg, a candidate for the Streptococcus pneumoniae ligase that attaches capsular polysaccharides to the bacterial cell wall, is directed to the division septum to ensure the full encapsulation of bacteria. Perturbation of this process result in bacteria with reduced protection from external peptidoglycan binding receptors (such as the pneumococcal major hydrolase) and impaired in their ability to survive within the infected host. [ABSTRACT FROM AUTHOR]