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

Abstract

Zidebactam and WCK 5153 are novel bicyclo-acyl hydrazide (BCH) agents that have previously been shown to act as ␤-lactam enhancer (BLE) antibiotics in Pseudomonas aeruginosa and Acinetobacter baumannii. The objectives of this work were to identify the molecular targets of these BCHs in Klebsiella pneumoniae and to investigate their potential BLE activity for cefepime and aztreonam against metallo-␤-lactamase (MBL)-producing strains in vitro and in vivo. Penicillin binding protein (PBP) binding profiles were determined by Bocillin FL assay, and 50% inhibitory concentrations (IC 50 s) were determined using ImageQuant TL software. MICs and kill kinetics for zidebactam, WCK 5153, and cefepime or aztreonam, alone and in combination, were determined against clinical K. pneumoniae isolates producing MBLs VIM-1 or NDM-1 (plus ESBLs and class C ␤-lactamases) to assess the in vitro enhancer effect of BCH compounds in conjunction with ␤-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effects in vivo. Zidebactam and WCK 5153 showed specific, high PBP2 affinity in K. pneumoniae. The MICs of BLEs were Ͼ64 g/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1 to Ͼ3 log 10 kill against MBL-producing K. pneumoniae strains. Furthermore, the bactericidal synergy observed for these BLE-␤-lactam combinations translated well into in vivo efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of the ␤-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors and display in vitro and in vivo BLE effects against multidrug-resistant (MDR) K. pneumoniae clinical isolates producing MBLs.

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

“…Possible treatment options includes cefiderocol (10) and the combination aztreonamavibactam (11,12). Combinations of β-lactams and β-lactam enhancers such as zidebactam (13) and nacubactam (14) have also shown promising activities. Moreover, several MBL inhibitors, including aspergillomarasmine A (15), dipicolinic acid derivatives (16), ANT431 (17), bisthiazolodines (18) and bismuth antimicrobials (19) have been reported.…”

The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

“…As zidebactam is a β-lactam 'enhancer', the cefepime-zidebactam combination also possesses activity against Enterobacteriaceae producing metallo-β-lactamases and class D oxacillinases and P. aeruginosa with metallo-βlactamases [120][121][122]. Zidebactam, referred to as a bicyclo-acyl hydrazide on the basis of its chemical scaffold, inhibits class A and C β-lactamases and PBP-2 of K. pneumoniae, P. aeruginosa, and A. baumannii [84,[123][124][125]. Despite poor in vitro activity (MICs 16-64 μg/mL) against A. baumannii, cefepime-zidebactam reduced bacterial burdens in neutropenic murine lung and thigh infection models with cefepime-resistant A. baumannii isolates [126,127].…”

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

“…142,143) Zidebactam, a diazabicyclooctane-class non-β-lactam antibiotic bearing a hydrazide moiety, exhibits a dual mechanism of action and high affinity for binding to penicillin-binding protein 2, resulting in the inhibition of Ambler class A and C β-lactamases. [144][145][146][147] Zidebactam also acts as a β-lactam enhancer when combined with cephalosporin. 148) While cefepime has antimicrobial activity against A. baumannii, 149) cefepime/zidebactam exhibits better antimicrobial activity against A. baumannii in vitro and in vivo than cefepime alone.…”