4.3 Mutations in CTX-M-type ESBLs

CTX-M-type ESBLs preferentially act on certain cephalosporin antibiotics. Cefotaxime is easily recognised and inactivated by CTX-M-type ESBLs while the bulkier cephalosporin ceftazidime is poorly recognised by CTX-M-type ESBLs (Bonnet, 2004). As a consequence, infections caused by bacteria that produce CTX-M-type ESBLs can be treated with ceftazidime. This specificity is based on the structure of the CTX-M β-lactam binding site which only allows the efficient recognition of penicillins, first-generation cephalosporins and cefotaxime (Figure 14) (Chen et al., 2005).

Figure 14 The structure of a CTX-M-type ESBL (Chen et al., 2005). The figure shows a ribbon diagram of a CTX-M-type ESBL protein structure. The ribbon shows the overall organisation of the protein giving a representation of the overall protein shape. The β-lactam binding site is indicated by the blue arrow. The amino acid mutation that increases the ceftazidimase activity of CTX-M is indicated by the blue star. You do not need to study this structure in detail.

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This figure shows a picture of the protein structure of a CTX-M-type ESBL. This structure is comprised of beta structures shown in yellow, alpha helices shown in pink and loop regions shown in white. The β-lactam binding site is indicated by the blue arrow. The amino acid mutation that increases the ceftazidimase activity of CTX-M is indicated by a blue star.

Figure 14 The structure of a CTX-M-type ESBL (Chen et al., 2005). The figure shows a ribbon diagram of a CTX-M-type ESBL protein ...

The specificity of CTX-M-type ESBLs can be modified by point mutations which improve the specificity of CTX-M-type ESBLs for ceftazidime. One of these mutations is indicated on Figure 14 (Cartelle et al., 2004). Altering this amino acid allows the bulkier ceftazidime to be more easily accommodated in the β-lactam binding site (Chen et al., 2005). Infections caused by bacteria producing this mutated version of the CTX-M-type ESBL are not treatable with ceftazidime. This CTX-M variant has been isolated from clinical strains of E. coli (Cartelle et al., 2004) and has probably been selected for the increasing use of ceftazidime in clinical practice.