Potent β-Lactam Enhancer Activity of Zidebactam and WCK 5153 against Acinetobacter baumannii, Including Carbapenemase-Producing Clinical Isolates

Abstract

Multidrug-resistant has rapidly spread worldwide, resulting in a serious threat to hospitalized patients. Zidebactam and WCK 5153 are novel non-β-lactam bicyclo-acyl hydrazide β-lactam enhancer antibiotics being developed to target multidrug-resistant The objectives of this work were to determine the 50% inhibitory concentrations (ICs) for penicillin-binding proteins (PBP), the OXA-23 inhibition profiles, and the antimicrobial activities of zidebactam and WCK 5153, alone and in combination with β-lactams, against multidrug-resistant MICs and time-kill kinetics were determined for an clinical strain producing the carbapenemase OXA-23 and belonging to the widespread European clone II of sequence type 2 (ST2). Inhibition of the purified OXA-23 enzyme by zidebactam, WCK 5153, and comparators was assessed. All of the compounds tested displayed apparent values of>100 μM, indicating poor OXA-23 β-lactamase inhibition. The ICs of zidebactam, WCK 5153, cefepime, ceftazidime, meropenem, and sulbactam (range of concentrations tested, 0.02 to 2 μg/ml) for PBP were also determined. Zidebactam and WCK 5153 demonstrated specific high-affinity binding to PBP2 of (0.01 μg/ml for both of the compounds). The MICs of zidebactam and WCK 5153 were>1,024 μg/ml for wild-type and multidrug-resistant strains. Importantly, combinations of cefepime with 8 μg/ml of zidebactam or WCK 5153 and sulbactam with 8 μg/ml of zidebactam or WCK 5153 led to 4- and 8-fold reductions of the MICs, respectively, and showed enhanced killing. Notably, several of the combinations resulted in full bacterial eradication at 24 h. We conclude that zidebactam and WCK 5153 are PBP2 inhibitors that show a potent β-lactam enhancer effect against, including a multidrug-resistant OXA-23-producing ST2 international clone.

In Vitro and In Vivo Activities of β-Lactams in Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae

“…Since BLEs were antibacterially inactive against the strains studied and also were noninhibitors of MBLs, the lowering of the MICs of PBP3 binding agents cefepime and aztreonam in combination with BLEs appears to be an outcome of inactivation of complementary PBPs, resulting in growth inhibition. In the past, PBP binding data of BLEs were published for E. coli, A. baumannii, and P. aeruginosa (14,15), while in the present study, for the first time, we demonstrate high-affinity binding to K. pneumoniae PBP2. The time-kill studies showed that both zidebactam and WCK 5153 enhanced the bactericidal activity of cefepime and aztreonam.…”

“…In an attempt to overcome the limitations of BLI-based combinations, a novel approach based on BLE has been proposed. In vitro and in vivo studies have shown that this approach has a potential to circumvent the need for ␤-lactamase inhibition and still provide clinically significant improved activity against organisms harboring any of the four classes of ␤-lactamases (14,15). Structure-activity relationship studies led to the identification of WCK 5107 (zidebactam) and WCK 5153 as potent ␤-lactam enhancers (22).…”

“…In previous works, our group has shown that two novel bicyclo-acyl hydrazide (BCH) ␤-lactam enhancers (BLEs), zidebactam and WCK 5153, selectively bind penicillin binding protein 2 (PBP2) of Acinetobacter baumannii and Pseudomonas aeruginosa (14,15). In these organisms, both compounds, through their PBP2 binding-driven ␤-lactam enhancer action, have demonstrated the ability to overcome several carbapenem resistance mechanisms in combination with ␤-lactams (13,(15)(16)(17).…”

The Novel β-Lactam Enhancer Zidebactam Augments the In Vivo Pharmacodynamic Activity of Cefepime in a Neutropenic Mouse Lung Acinetobacter baumannii Infection Model

“…WCK 5222 is a combination of cefepime (FEP) and the ␤-lactam enhancer antibiotic zidebactam (ZID), which is based on a novel bicycloacyl hydrazide pharmacophore derived from diazabicyclooctane. The combination operates through a novel mechanism of action involving the concomitant inactivation of multiple penicillin binding proteins (PBPs) (5,6). As a result, the FEP-ZID combination circumvents the need for ␤-lactamase inhibition and has been shown to be active against all four classes of ␤-lactamase producers (7).…”

“…Though ZID inhibits certain class A and C ␤-lactamases, however, it is not an inhibitor of class B ␤-lactamases and the A. baumannii-associated class D carbapenemases. Zidebactam's PBP2 binding in A. baumannii was evidenced through spheroplast formation upon exposure to low concentrations of ZID (5,8,9), as well as through cell-free PBP-binding studies (5,6,8,9). Studies have shown that FEP causes PBP3 inactivation at sublethal concentrations, even in the presence of FEP-hydrolyzing ␤-lactamases, which is manifested as cell elongation.…”