Staphylococcal Peptidoglycan Interpeptide Bridge Biosynthesis: A Novel Antistaphylococcal Target?

Abstract

In staphylococci, crosslinking of the peptide moiety of peptidoglycan is mediated via an additional spacer, the interpeptide bridge, consisting of five glycine residues. The femAB operon, coding for two approximately 50-kDa proteins is known to be involved in pentaglycine bridge formation. Using chemical mutagenesis of the beta-lactam-resistant strain BB270 and genetic, biochemical, and biophysical characterization of mutants selected for loss of beta-lactam resistance and reduced lysostaphin sensitivity it is shown that peptide bridge formation proceeds via three intermediate bridge lengths (cell wall peptides with no, one, three, and five glycine units). To proceed from one intermediate to the next, three genes appear necessary: femX, femA, and femB. The drastic loss of beta-lactam resistance after inactivation of FemA or partial impairment of FemX even beyond the level of the sensitive wild-type strains renders these proteins attractive antistaphylococcal targets.

Identification of three additional femAB-like open reading frames in Staphylococcus aureus

“…In contrast, FmhB, the most distantly related of the three new factors, seemed essential for growth, as was also recently observed by Tang et al [19]. Because of its relatedness to FemA and FemB and its apparent essentiality, FmhB may be the factor FemX predicted to be involved in the addition of the ¢rst glycine to the peptidoglycan O-L-lysine [3]. It may also correspond to the femAB-like factor identi¢ed in a murine model of bacteremia shown to be required for virulence, as were also femA and femB [20].…”

“…They presumably catalyze and/or control the incorporation of Gly2-Gly3 (FemA), and Gly4-Gly5 (FemB). A third factor (FemX) responsible for the attachment of the ¢rst glycine residue to the O-amino group of lysine of the nascent interpeptide has been postulated [3]. Because of similar functions, FemX was speculated to have some sequence similarity with FemA and FemB.…”

Application of a bacterial two-hybrid system for the analysis of protein–protein interactions between FemABX family proteins

“…The protein-protein interactions we were able to show add to the more-detailed knowledge about the FemABX protein family that has been gained in recent years (Benson et al, 2002;Bouhss et al, 2002;reviewed by Rohrer & BergerBächi, 2003). Proteins of the FemABX family are a recognized target for the development of novel antimicrobial agents (Kopp et al, 1996). It is therefore crucial to understand all aspects of their function in order to advance towards the development of new medicines.…”

Synthesis of Mosaic Peptidoglycan Cross-bridges by Hybrid Peptidoglycan Assembly Pathways in Gram-positive Bacteria

“…Deletion of bppA2 led to production of precursors substituted by a single L-Ala and to impaired expression of intrinsic ␤-lactam resistance (14). For these reasons, transferases of the Fem family are considered to be potential targets for the development of novel antibiotics active against ␤-lactam-resistant Gram-positive cocci (15).…”