β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Abstract

The biological diversity of the unicellular bacteriawhether assessed by shape, food, metabolism, or ecological nichesurely rivals (if not exceeds) that of the multicellular eukaryotes. The relationship between bacteria whose ecological niche is the eukaryote, and the eukaryote, is often symbiosis or stasis. Some bacteria, however, seek advantage in this relationship. One of the most successfulto the disadvantage of the eukaryoteis the small (less than 1 μm diameter) and nearly spherical Staphylococcus aureus bacterium. For decades, successful clinical control of its infection has been accomplished using β-lactam antibiotics such as the penicillins and the cephalosporins. Over these same decades S. aureus has perfected resistance mechanisms against these antibiotics, which are then countered by new generations of β-lactam structure. This review addresses the current breadth of biochemical and microbiological efforts to preserve the future of the β-lactam antibiotics through a better understanding of how S. aureus protects the enzyme targets of the β-lactams, the penicillin-binding proteins. The penicillin-binding proteins are essential enzyme catalysts for the biosynthesis of the cell wall, and understanding how this cell wall is integrated into the protective cell envelope of the bacterium may identify new antibacterials and new adjuvants that preserve the efficacy of the β-lactams.

Accumulation of Succinyl Coenzyme A Perturbs the Methicillin-Resistant Staphylococcus aureus (MRSA) Succinylome and Is Associated with Increased Susceptibility to Beta-Lactam Antibiotics

“…The discovery that Atl was the most succinylated protein in the MRSA proteome and that 12 of the 82 succinyl-lysines were significantly more succinylated in the sucC mutant suggested a potential connection to reduced β-lactam resistance. Fisher and Mobashery recently proposed a model in which the bactericidal activity of β-lactams is the result of deregulated Atl activity at the cell division septum ( 59 ). Our data showing that autolytic activity was significantly reduced in the sucC mutant and that the oxacillin MIC of the atl transposon mutant NE460 was unchanged are not consistent with this possibility.…”

Drugs That Changed Society: History and Current Status of the Early Antibiotics: Salvarsan, Sulfonamides, and β-Lactams

“…As a consequence, penicillin reacts freely with alcohols. In penicillin-binding peptides a serine residue in the active site is esterified by the penicillins [ 52 ]. Other examples of reactive cyclic amides are known (see Section 9 ) [ 53 ].…”

“…The cell wall or cell envelope is and essential polymer surrounding and enclosing bacteria, Defects in the polymer might be lethal [ 52 ]. Several enzymes and transporters are involved in the construction of the cell wall including several penicillin-binding peptides (PBP).…”

“…Several enzymes and transporters are involved in the construction of the cell wall including several penicillin-binding peptides (PBP). The cell wall of Staphylococcus aureus is fortified by crosslinking strands of peptidoglycans with strands of peptides as illustrated by the cartoon shown in Figure 7 [ 52 , 58 ]. The L-lysine residue is replaced with meso-diaminopimelic acid in other bacteria [ 44 ].…”

A synthetic 5,3-cross-link in the cell wall of rod-shaped Gram-positive bacteria

“…While variability in the sequence of the peptide stem exists across species, the archetypal structure of the monoderm stem is L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala, and in the diderm L-Lys is typically substituted with the carboxy derivative meso-2,6-diaminopimelate (m-DAP) (Fig. 1B) (3,4). The peptide stems of the cell wall are cross-linked by penicillinbinding protein (PBP) D,D-transpeptidases, and L,D-transpeptidases.…”