Bicyclic Boronate β‐Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

Lence, Emilio; González‐Bello, Concepción

doi:10.1002/adtp.202000246

Cited by 19 publications

(32 citation statements)

References 156 publications

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“…A number of boron-based chemicals are known as therapeutic agents or drugs, such as Ixazomib, Tavaborole , Crisaborole, Vaborbactam or Taniborbactam (VNRX-5133) Ban et al (2015) , Thareja et al (2017) , Krajnc et al (2019a) , Krajnc et al (2019b) , Lang et al (2020) , Lence and Gonzales-Bello (2021) , for specifications see e.g. Drug Central 2021, https://drugcentral.org/ .…”

Section: Introductionmentioning

confidence: 99%

“…Until now, most of the covalent docking work has been supported by heuristic procedures Krajnc et al (2019a) , Krajnc et al (2019b) , and only a few studies of this type of process have been described based on approximate quantum-mechanical methods e.g. ( Sgrignani et al, 2015 ; Krivitskaya and Khrenova, 2021 ; Lence and Gonzalez-Bello, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

Charzewski

Krzyśko

Lesyng

2021

Front. Mol. Biosci.

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Recently, molecular covalent docking has been extensively developed to design new classes of inhibitors that form chemical bonds with their biological targets. This strategy for the design of such inhibitors, in particular boron-based inhibitors, holds great promise for the vast family of β-lactamases produced, inter alia, by Gram-negative antibiotic-resistant bacteria. However, the description of covalent docking processes requires a quantum-mechanical approach, and so far, only a few studies of this type have been presented. This study accurately describes the covalent docking process between two model inhibitors - representing two large families of inhibitors based on boronic-acid and bicyclic boronate scaffolds, and three β-lactamases which belong to the A, C, and D classes. Molecular fragments containing boron can be converted from a neutral, trigonal, planar state with sp2 hybridization to the anionic, tetrahedral sp3 state in a process sometimes referred to as morphing. This study applies multi-scale modeling methods, in particular, the hybrid QM/MM approach which has predictive power reaching well beyond conventional molecular modeling. Time-dependent QM/MM simulations indicated several structural changes and geometric preferences, ultimately leading to covalent docking processes. With current computing technologies, this approach is not computationally expensive, can be used in standard molecular modeling and molecular design works, and can effectively support experimental research which should allow for a detailed understanding of complex processes important to molecular medicine. In particular, it can support the rational design of covalent boron-based inhibitors for β-lactamases as well as for many other enzyme systems of clinical relevance, including SARS-CoV-2 proteins.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

Charzewski

Krzyśko

Lesyng

2021

Front. Mol. Biosci.

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“…Accordingly, the enzyme loop that surrounds both ions (bottom of the active site), namely L10, needs to have some flexibility to facilitate the distancing. We have shown recently that while the active site lid, namely L3 loop, is quite flexible for the three enzymes, IMP-1, NDM-1, and VIM-2, significant differences were identified in the bottom of their active sites ( Figure 7A ; Lence and González-Bello, 2021 ). Thus, IMP-1 showed to be the enzyme with the least flexible L10 loop of the three, as barely any motion of this area was observed during simulation.…”

Section: Resultsmentioning

confidence: 92%

Molecular Basis of Bicyclic Boronate β-Lactamase Inhibitors of Ultrabroad Efficacy – Insights From Molecular Dynamics Simulation Studies

Lence

González‐Bello

2021

Front. Microbiol.

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β-Lactam antibiotics represent about 70% of all antibacterial agents in clinical use. They are safe and highly effective drugs that have been used for more than 50 years, and, in general, well tolerated by most patients. However, its usefulness has been dramatically reduced with the spread and dissemination worldwide of multi-drug resistant bacteria. These pathogens elude the therapeutic action of these antibiotics by expressing β-lactamase enzymes that catalyze the hydrolysis of their β-lactam ring to give inactive products, which is one of the most relevant resistance mechanisms in deadly pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae. From the drug development point of view, the design of an efficient β-lactamase inhibitor able to block this antibiotic resistance mechanism and restore β-lactam antibiotics efficacy is challenging. This is due to: (1) the huge structural diversity of these enzymes in both the amino acid sequence and architecture of the active site; (2) the distinct hydrolytic capability against different types of substrates; (3) the variety of enzyme mechanisms of action employed, either involving covalent catalyzed processes (serine hydrolases) or non-covalent catalysis (zinc-dependent hydrolases); and (4) the increasing emergence and spread of bacterial pathogens capable of simultaneously producing diverse β-lactamases. Hence, a long-pursued goal has been the development of ultrabroad-spectrum inhibitors able to inhibit both serine- and metallo-β-lactamases. The recent development of taniborbactam (formerly VNRX-5133) and QPX7728, which are bicyclic boronate inhibitors currently under clinical development, represents a huge step forward in this goal. In this article, the molecular basis of the ultrabroad-spectrum of activity of these boron-based inhibitors is analyzed by molecular dynamics simulation studies using the available crystal structures in complex with both inhibitors, or the models constructed from wild-type forms. The efficacy of taniborbactam and QPX7728 is compared with the cyclic boronate inhibitor vaborbactam, which is the first boron-based β-lactamase inhibitor approved by the FDA in combination with meropenem for the treatment of complicated urinary tract infections.

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“…Taniborbactam: Taniborbactam (VNRX-5133) [105] is a cyclic boronic acid derivative that is now in clinical trials. It has been identified as a pan spectrum inhibitor of both SBLs and MBLs.…”

Section: Cyclic Boronatesmentioning

confidence: 99%

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

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Bicyclic Boronate β‐Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

Cited by 19 publications

References 156 publications

Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

Molecular Basis of Bicyclic Boronate β-Lactamase Inhibitors of Ultrabroad Efficacy – Insights From Molecular Dynamics Simulation Studies

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

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