In vitro and in vivo activity of {beta}-lactams in combination with novel {beta}-lactam enhancers, zidebactam and WCK 5153, against multidrug-resistant metallo-{beta}-lactamase producing Klebsiella pneumoniae [Mechanisms of Action]

Zidebactam and WCK 5153 are novel Bicyclo-acyl Hydrazides (BCH) agents that have previously been shown to act as β-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 on cefepime and aztreonam against metallo-β-lactamase (MBL) -producing strains in vitro and in vivo. PBP-binding profiles were determined by BOCILLIN FL assay, and 50% inhibitory concentrations (IC₅₀) were determined using the 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- blaVIM-1 or blaNDM-1 (+ ESBLs and class C) to assess the in vitro enhancer effect of BCH compounds in conjunction with β-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effect in vivo. Zidebactam and WCK 5153 showed specific, high PBP2 affinity in K. pneumoniae. MICs of BLEs were >64 μg/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1->3 log₁₀-kill against MBL-producing K. pneumoniae strains. Furthermore, the bactericidal synergy observed for these BLE-BL combinations translated well into in vivo efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of β-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors, and display in vitro and in vivo BLE effect against MDR K. pneumoniae clinical isolates producing MBLs.

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