WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent “β-Lactam Enhancer” Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones

Moyá, Bartolomé; Barceló, Isabel; Bhagwat, Sachin; Patel, Mahesh; Bou, Germán; Papp-Wallace, Krisztina M.; Bonomo, Robert A.; Oliver, Antonio

doi:10.1128/aac.02529-16

Cited by 98 publications

(122 citation statements)

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“…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.…”

Section: Discussionsupporting

confidence: 68%

“…Cefepime MICs were higher for all of the strains. Zidebactam and WCK 5153 do not possess ␤-lactamase-inhibitory activity against MBL enzymes (15). In the present study, neither BLE showed significant antibacterial activity against the K. pneumoniae strains tested.…”

Section: Discussioncontrasting

confidence: 59%

“…In the present study, neither BLE showed significant antibacterial activity against the K. pneumoniae strains tested. However, these BLEs were shown to induce spheroplast formation at sub-MICs (15). Such morphological change is evidence for BLE-mediated PBP2 dysfunction without concomitant growth inhibition.…”

Section: Discussionmentioning

confidence: 93%

“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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). In the present study, we show for the first time the PBP binding profiles of BCH compounds and comparators for another clinically significant pathogen, K. pneumoniae, and the synergistic bactericidal action of these BLEs in combination with ␤-lactams (cefepime and aztreonam).…”

mentioning

confidence: 99%

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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

Moyá

Barceló

Cabot

et al. 2019

Antimicrob Agents Chemother

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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.

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Section: Discussionsupporting

confidence: 68%

Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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

Moyá

Barceló

Cabot

et al. 2019

Antimicrob Agents Chemother

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Combating Multidrug‐Resistant Bacteria by Integrating a Novel Target Site Penetration and Receptor Binding Assay Platform Into Translational Modeling

Lang

Shah

Tao

et al. 2021

Clin Pharma and Therapeutics

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Multidrug-resistant bacteria are causing a serious global health crisis. A dramatic decline in antibiotic discovery and development investment by pharmaceutical industry over the last decades has slowed the adoption of new technologies. It is imperative that we create new mechanistic insights based on latest technologies, and use translational strategies to optimize patient therapy. Although drug development has relied on minimal inhibitory concentration testing and established in vitro and mouse infection models, the limited understanding of outer membrane permeability in Gramnegative bacteria presents major challenges. Our team has developed a platform using the latest technologies to characterize target site penetration and receptor binding in intact bacteria that inform translational modeling and guide new discovery. Enhanced assays can quantify the outer membrane permeability of β-lactam antibiotics and β-lactamase inhibitors using multiplex liquid chromatography tandem mass spectrometry. While β-lactam antibiotics are known to bind to multiple different penicillin-binding proteins (PBPs), their binding profiles are almost always studied in lysed bacteria. Novel assays for PBP binding in the periplasm of intact bacteria were developed and proteins identified via proteomics. To characterize bacterial morphology changes in response to PBP binding, high-throughput flow cytometry and time-lapse confocal microscopy with fluorescent probes provide unprecedented mechanistic insights. Moreover, novel assays to quantify cytosolic receptor binding and intracellular drug concentrations inform target site occupancy. These mechanistic data are integrated by quantitative and systems pharmacology modeling to maximize bacterial killing and minimize resistance in in vitro and mouse infection models. This translational approach holds promise to identify antibiotic combination dosing strategies for patients with serious infections.

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Structure activity relationship (SAR) driven design and discovery of WCK 5107 (Zidebactam): novel β-lactam enhancer, potent against multidrug-resistant gram-negative pathogens

et al. 2023

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WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent “β-Lactam Enhancer” Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones

Cited by 98 publications

References 50 publications

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

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

Combating Multidrug‐Resistant Bacteria by Integrating a Novel Target Site Penetration and Receptor Binding Assay Platform Into Translational Modeling

Structure activity relationship (SAR) driven design and discovery of WCK 5107 (Zidebactam): novel β-lactam enhancer, potent against multidrug-resistant gram-negative pathogens

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