6bn3

Publication Abstract from PubMed

The diazabicyclooctane (DBO) inhibitor avibactam (AVI) reversibly inactivates most serine beta-lactamases, including the CTX-M beta-lactamases. Currently, more than 230 unique CTX-M members distributed in five clusters with less than 5% amino acid sequence divergence within each group have been described. Recently, a variant named CTX-M-151 was isolated from a Salmonella enterica subsp. enterica serovar Choleraesuis strain in Japan. This variant possesses a low degree of amino acid identity with the other CTX-Ms (63.2% to 69.7% with respect to the mature proteins), and thus it may represent a new subgroup within the family. CTX-M-151 hydrolyzes ceftriaxone better than ceftazidime (k cat/K m values 6,000-fold higher), as observed with CTX-Ms. CTX-M-151 is well inhibited by mechanism-based inhibitors like clavulanic acid (inactivation rate [k inact]/inhibition constant [Ki ] = 0.15 muM(-1) . s(-1)). For AVI, the apparent inhibition constant (Ki app), 0.4 muM, was comparable to that of KPC-2; the acylation rate (k2/K) (37,000 M(-1) . s(-1)) was lower than that for CTX-M-15, while the deacylation rate (k off) (0.0015 s(-1)) was 2- to 14-fold higher than those of other class A beta-lactamases. The structure of the CTX-M-151/AVI complex (1.32 A) reveals that AVI adopts a chair conformation with hydrogen bonds between the AVI carbamate and Ser70 and Ser237 at the oxyanion hole. Upon acylation, the side chain of Lys73 points toward Ser130, which is associated with the protonation of Glu166, supporting the role of Lys73 in the proton relay pathway and Glu166 as the general base in deacylation. To our knowledge, this is the first chromosomally encoded CTX-M in Salmonella Choleraesuis that shows similar hydrolytic preference toward cefotaxime (CTX) and ceftriaxone (CRO) to that toward ceftazidime (CAZ).

Structural and Biochemical Characterization of the Novel CTX-M-151 Extended-Spectrum beta-Lactamase and Its Inhibition by Avibactam.,Ghiglione B, Rodriguez MM, Brunetti F, Papp-Wallace KM, Yoshizumi A, Ishii Y, Bonomo RA, Gutkind G, Klinke S, Power P Antimicrob Agents Chemother. 2021 Mar 18;65(4). pii: AAC.01757-20. doi:, 10.1128/AAC.01757-20. Print 2021 Mar 18. PMID:33431411^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.