An active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M β-lactamase drug-resistance enzymes

Shuo Lu, Liya Hu, Hanfeng Lin, Allison Judge, Paola Rivera, Murugesan Palaniappan, Banumathi Sankaran, Jin Wang, B. V. Venkataram Prasad and Timothy Palzkill ()
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Shuo Lu: Department of Pharmacology and Chemical Biology, Baylor College of Medicine
Liya Hu: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine
Hanfeng Lin: Department of Pharmacology and Chemical Biology, Baylor College of Medicine
Allison Judge: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine
Paola Rivera: Department of Pharmacology and Chemical Biology, Baylor College of Medicine
Murugesan Palaniappan: Baylor College of Medicine
Banumathi Sankaran: Lawrence Berkeley National Laboratory
Jin Wang: Department of Pharmacology and Chemical Biology, Baylor College of Medicine
B. V. Venkataram Prasad: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine
Timothy Palzkill: Department of Pharmacology and Chemical Biology, Baylor College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract β-lactamases inactivate β-lactam antibiotics leading to drug resistance. Consequently, inhibitors of β-lactamases can combat this resistance, and the β-lactamase inhibitory protein (BLIP) is a naturally occurring inhibitor. The widespread CTX-M-14 and CTX-M-15 β-lactamases have an 83% sequence identity. In this study, we show that BLIP weakly inhibits CTX-M-14 but potently inhibits CTX-M-15. The structure of the BLIP/CTX-M-15 complex reveals that binding is associated with a conformational change of an active site loop of β-lactamase. Surprisingly, the loop structure in the complex is similar to that in a drug-resistant variant (N106S) of CTX-M-14. We hypothesized that the pre-established favorable loop conformation of the N106S mutant would facilitate binding. The N106S substitution results in a ~100- and 10-fold increase in BLIP inhibition potency for CTX-M-14 and CTX-M-15, respectively. Thus, this indicates that an active site loop in β-lactamase toggles between conformations that control antibiotic hydrolysis and inhibitor susceptibility. These findings highlight the role of accessible active site conformations in controlling enzyme activity and inhibitor susceptibility as well as the influence of mutations in selectively stabilizing discrete conformations.

Date: 2022
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DOI: 10.1038/s41467-022-34564-3

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