Abstract
The cefotaximase or CTX-M, family of serine-β-lactamases represents a significant clinical concern due to the ability for these enzymes to confer resistance to a broad array of β-lactam antibiotics an inhibitors. This behavior lends CTX-M-ases to be classified as extended spectrum β-lactamases (ESBL). Across the family of CTX-M-ases most closely related to CTX-M-1, the structures of CTX-M-15 with a library of different ligands have been solved and serve as the basis of comparison within this review. Herein we focus on the structural changes apparent in structures of CTX-M-15 in complex with diazabicyclooctane (DABCO) and boronic acid transition state analog inhibitors. Interactions between a positive surface patch near the active site and complementary functional groups of the bound inhibitor play key roles in the dictating the conformations of active site residues. The insights provided by analyzing structures of CTX-M-15 in complex with DABCO and boronic acid transition state analog inhibitors and analyzing existing structures of CTX-M-64 offer opportunities to move closer to making predictions as to how CTX-M-ases may interact with potential drug candidates, setting the stage for the further development of new antibiotics and β-lactamase inhibitors.
Highlights
The use of β-lactam-based antibiotics has created substantial evolutionary pressure on bacteria
CTX-M-ases feature a catalytic serine at Ambler position 70 that hydrolyze β-lactam containing antibiotics after acylation
It was later discovered that CTX-M-1 was identified, named, and characterized in parallel as MEN-1, as subsequent genetic sequencing revealed that these two enzymes were entirely identical (Barthélémy et al, 1992)
Summary
The use of β-lactam-based antibiotics has created substantial evolutionary pressure on bacteria. The sidechain of N104 in the apo structure of CTX-M-15 is located spatially near the sidechain of N132, a residue within the SDN-loop These two residues comprise a portion of the cationic patch in the active site that interacts with carboxamide carbonyl oxygens attached to the core β-lactam architecture (Lahiri et al, 2013). The lack of a possible route for forming polar contacts with residue 104 in KPC-2, and the positioning of the backbone atoms of residue 237 (Figure 5B), provides less stable interactions with the carboxamide and it’s substituents, which may explain some of the observed differences in the binding characteristics of DABCO drugs in members of the KPC family and that of CTX-M (Ehmann et al, 2013) (Figure 5).
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