WhyD tailors surface polymers to prevent premature bacteriolysis and direct cell elongation in Streptococcus pneumoniae

Abstract

Penicillin and related antibiotics disrupt cell wall synthesis in bacteria causing the downstream misactivation of cell wall hydrolases called autolysins to induce cell lysis. Despite the clinical importance of this phenomenon, little is known about the factors that control autolysins and how penicillins subvert this regulation to kill cells. In the pathogen Streptococcus pneumoniae (Sp), LytA is the major autolysin responsible for penicillin-induced bacteriolysis. We recently discovered that penicillin treatment of Sp causes a dramatic shift in surface polymer biogenesis in which cell wall-anchored teichoic acids (WTAs) increase in abundance at the expense of lipid-linked teichoic acids (LTAs). Because LytA binds to both species of teichoic acids, this change recruits the enzyme to its substrate where it cleaves the cell wall and elicits lysis. In this report, we identify WhyD (SPD_0880) as a new factor that controls the level of WTAs in Sp cells to prevent LytA misactivation during exponential growth and premature lysis. We show that WhyD is a WTA hydrolase that restricts the WTA content of the wall to areas adjacent to active PG synthesis. Our results support a model in which the WTA tailoring activity of WhyD during exponential growth directs PG remodeling activity required for proper cell elongation in addition to preventing autolysis by LytA.

Interrogation of the contribution of (endo)lysin domains to tune their bacteriolytic efficiency provides a novel clue to design superior antibacterials

“…On the other hand, the almost null QLAS activity on bacteria would likely result from the combination of the less bacterium-efficient EAD of LytA with the lower affinity CBD of Skl. In this respect, it is known that the EAD of LytA recognizes the nascent PG as the cleavable substrate, the accessibility of which is drastically limited in intact cells before the stationary phase [29]. Besides, preferential localization of LytA at the equatorial position of the cellwhere the nascent PG is synthesizedseems to require the concerted action of its EAD and CBD.…”

“…The activity of lysins in their natural environment (lysis-fromwithin) must be strictly spatiotemporally controlled to prevent unwanted lysis of the cell wall from compromising either phage replication or bacterial survival, and a variety of regulatory mechanisms have been described [18,21,[26][27][28][29][30][31][32]. Yet, such control may not be optimal when bacterial elimination is the objective, and the design of lysins with improved therapeutic potential could benefit from a better understanding of how domain cross-talk may contribute to either speeding up or slowing down the lysis of bacteria.…”

Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review

“…PLY is produced constitutively but free toxin is higher in the late log phase due to the presence of a defined threshold concentration of extracellular autolysin (LytA) which dictates the onset of autolysis. The entry into the stationary phase due to nutrient depletion sensitizes cells to the effect of LytA, while during exponential growth they are protected from the action of this enzyme [ 10 , 11 ]. Other investigations have also revealed the release of PLY in the extracellular vesicles [ 12 ].…”