Sandbox Reserved 1488

Penicillin-binding proteins (PBPs) have been scrutinized for over 40 years. Recent structural information on PBPs together with the ongoing long-term biochemical experimental investigations, and results from more recent techniques such as protein localization by green fluorescent protein-fusion immunofluorescence or double-hybrid assay, have brought our understanding of the last stages of the peptidoglycan biosynthesis to an outstanding level that allows a broad outlook on the properties of these enzymes. Details are emerging regarding the interaction between the peptidoglycan-synthesizing PBPs and the peptidoglycan, their mesh net-like product that surrounds and protects bacteria^[1].

Function

The bacterial cell wall is essential for cell survival. It is composed of layers of peptidoglycan modified with proteins and polymers. In bacteria, this peptidoglycan layer is formed by the coordinated action of multiple proteins, including penicillin-binding proteins (PBPs). PBPs are transpeptidases, carboxypeptidases and endopeptidases that synthesize new and remodel existing peptidoglycan.

PBPs are classified by their enzymatic activity:

(1) class A, bifunctional PBPs with both glycosyltransferase and transpeptidase activities;

(2) class B, transpeptidases; and

(3) class C, carboxy-peptidases and endopeptidases.

Disease

Enterococci exhibits tolerance to the bactericidal activity of β-lactams ^[2] , a phenomenon that compromises the use of β-lactam antibiotics as single agents in the treatment of enterococcal endocarditis ^[3]. As a consequence, multi-resistant E. faecium and E. faecalis represent one of the most dangerous threats in infectious diseases therapeutics.

Rare strains of E. faecalis and most nosocomial strains of E. faecium exhibit even higher levels of resistance to penicillins, effectively eliminating β-lactams as a treatment option ^[4]. Of greater concern is the observation that prolonged β-lactam therapy can lead to the emergence of highly resistant strains.

Structure

Structural insights into β-lactam resistance

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