3.2.1 PBP2a – a PBP that doesn’t bind cephalosporins

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to most β-lactam antibiotics, including cephalosporins. This is one of the reasons why infections caused by MRSA are extremely challenging to treat. This resistance results from the expression of penicillin-binding protein 2a (PBP2a). PBP2a binds β-lactams more poorly than other PBPs because differences in its structure prevent β-lactam antibiotics from reaching the binding site (Figure 5).

Figure 5 The protein structure of PBP2a. The figure shows a ribbon diagram of the PBP2a protein structure. The ribbon shows the overall organisation of the protein giving a representation of the overall protein shape. The ß-lactam binding site (indicated with an arrow) is inaccessible to ß-lactam antibiotics because of changes to the structure of PBP2a (see Figure 2 in Section 1.1) (Lim and Strynadka, 2002). You do not need to study this structure in detail.

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This figure shows a picture of the protein structure of PBP2a. This structure is comprised of beta structures shown in yellow, alpha helices shown in pink and loop regions shown in white. The binding site for β-lactam antibiotics is indicated with an arrow.

Figure 5 The protein structure of PBP2a. The figure shows a ribbon diagram of the PBP2a protein structure. The ribbon shows the overall ...

You may recall from Week 2 that cephalosporins exert their bactericidal action by binding to penicillin-binding proteins and preventing them from cross-linking the bacterial cell wall. Since cephalosporins do not bind to PBP2a, its presence in MRSA allows cell wall biosynthesis to occur in the presence of most cephalosporins.

Fortunately, more recently developed cephalosporins, including ceftaroline (Duplessis and Crum-Cianflone, 2011) and ceftobiprole (Kisgen and Whitney, 2008) can bind to and inhibit the activity of PBP2a. These cephalosporins have been licensed for the treatment of community- and hospital-acquired pneumonia and complicated skin and soft tissue infections (NICE, 2017).

You will learn more about the development of cephalosporin antibiotics in Week 6.