Taniborbactam Effectively Inhibits Pseudomonas-Derived Cephalosporinase

Pseudomonas-derived cephalosporinase (PDC) is a class C β-lactamase in P aeruginosa. PDC-88 is a variant characterized by a Thr-Pro amino acid deletion in the R2-loop. With this deletion, cefepime (FEP), ceftazidime (CAZ), and ceftolozane-tazobactam (TOL/TZB) susceptibility is reduced. However, the mechanism for this “gain of function” is unknown.

A study presented virtually at the annual IDWeek conference investigated taniborbactam (TAN), a novel cyclic boronate β-lactamase inhibitor (BLI) that works against all four β-lactamase classes. TAN is also currently undergoing a phase 3 clinical trial paired with FEP. In the study, presented by Andrew R. Mack, the investigators studied the extended-spectrum AmpC (ESAC) phenotype of PDC-88 to explore the ability of TAN to inhibit the variant.

The investigators determined broth microdilution minimum inhibitory concentrations (MIC) in accordance with CLSI. They purified PDC-3 and PDC-88 and determined steady-state enzyme kinetics. Finally, they conducted quadrupole time-of-flight mass spectrometry (Q-TOF-MS).

The results showed that in isogenic E coli with PDC-3, FEP MIC increased 8-fold, and in E coli with PDC-88, FEP MIC increased 128-fold. Adding TAN at 4 μg/ml restored FEP activity and lowered MIC to 0.25 μg/ml in PDC-3 and PDC-88 strains. According to the abstract, “PDC-88 demonstrated a 9-fold lower KM, 3.4-fold lower kcat, and 2.6-fold higher kcat/KM for FEP compared to PDC-3. TAN Ki values were 4- to 10-fold lower than avibactam (AVI) and 40- to 95-fold lower than TZB. The TAN acylation constant (k2/K) was 7- to 12-fold greater than AVI and 133- to 366-fold higher than TZB. Q-TOF-MS revealed faster deacylation of FEP by PDC-88 compared to TOL and CAZ. TOL was acylated and deacylated by PDC-88 but not by PDC-3.CAZ was readily acylated but slowly deacylated by PDC-88 compared to PDC-3.”

In all variants, taniborbactam and avibactam restored susceptibility, while tazobactam was less effective against PDC-88 and variants. Different kinetic constants caused the elevated cephalosporin MICs.The results led the investigators to postulate that PDC-88 increases FEP MIC by enhanced hydrolysis, TOL MICs by enabling acylation, and CAZ MICs by both trapping and enhancing hydrolysis. TAN inhibits both PDC-3 and PDC-88 with similar kinetic profiles, and appears to be a more efficient inhibitor of PDC than current BLIs used to combat P. aeruginosa. They concluded that combining TAN and FEP may be a vital treatment option for P. aeruginosa isolates that develop ESAC phenotypes.