Insights into cell wall synthesis and cell division in Staphylococcus aureus

Dissertation presented to obtain the Ph.D degree in Biology

Staphylococcus aureus is a gram-positive bacterial pathogen that besides persistently colonizing healthy individuals, is responsible for a large number of hospital-associated bacterial infections. The extraordinary capacity of S. aureus to acquire resistance to antibiotics led to the emergence of highly resistant strains, mainly methicillin-resistant S. aureus (MRSA) strains, that are a major cause of soft skin and tissue infections and bacteremia. In one third of European countries, including Portugal, more than 25% of S. aureus infections are caused by MRSA strains. The capacity of MRSA strains to resist β-lactam antibiotics (such as penicillin) is mainly due to the acquisition of an extra-species penicillin-binding protein (PBP), PBP2A. PBPs are bacterial enzymes involved in the synthesis of the cell wall polymer peptidoglycan. Besides PBP2A, which is present only in MRSA strains, S. aureus has 4 native PBPs (PBP1-4), which catalyze the polymerization (transglycosylation) and the cross-linking (transpeptidation) of glycan chains, forming a strong yet flexible structure that protects the cell from the high internal osmotic pressure. Peptidoglycan is unique to the bacterial kingdom and its biosynthesis is the target of a vast number of clinically important antibiotics such as β-lactams and glycopeptides. β-lactam antibiotics target the transpeptidase domain of PBPs, halting peptidoglycan synthesis and eventually leading to cell lysis. However, in MRSA strains the existence of PBP2A, which has a low affinity for β-lactams, enables cell wall synthesis to continue even in the presence of these antibiotics. Under these conditions, the transpeptidase domain of PBP2A functionally cooperates with the transglycosylase domain of the unique bifunctional PBP, PBP2, to ensure continued cell wall synthesis and cell survival.(...)