Alkylidene Oxapenem β-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges

Miller, M.D.; Kale, Manoj; Reddy, K. Narender; Tentarelli, Sharon; Zambrowski, M.; Zhang, Minli; Palmer, Tiffany; Breen, John; Lahiri, S. C.; Shirude, Pravin S.; Verheijen, Jeroen C.

doi:10.1021/ml5001855

Cited by 6 publications

(4 citation statements)

References 18 publications

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“…In this regard, the existing literature suggests that there might be other promising inhibitor templates beyond the classical β-lactams and the DBOs. For example, oxapenems [154,179,180], such as AM-112, are potent β-lactamase inhibitors, though their synthesis is also challenging. Further, there is clearly scope for the development of new types of antibacterial-forming acyl-enzyme type complexes, perhaps based on natural products/inhibitors of nucleophilic serine (or nucleophilic cysteine) enzymes, such as lactivicins [111], trans-lactams [101] or compounds operating via an analogous mechanism of action, but which have been developed in other fields, for example, agrochemistry such as strigolactones [157] ( Figure 10).…”

Section: Future Perspectivementioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

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Section: Future Perspectivementioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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“…However, to afford OO bond cleavage, four electrons are required, suggesting that O 2 reduction proceeds through cooperative substrate activation by two molecules of 2-V 6 O 6 − (Scheme 3). To ensure the restored oxygen atom was not a result of cluster degradation, 1 atm of 18 792, Figure S12). A separate control experiment confirms that degradation of 2-V 6 O 6 − does not occur under the relevant reaction conditions, indicating substrate is required for the formation of 1-V 6 O 7 − (Figure S13).…”

mentioning

confidence: 99%

Oxygen-Atom Vacancy Formation at Polyoxovanadate Clusters: Homogeneous Models for Reducible Metal Oxides

2018

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We report the first example of oxygen-atom vacancy formation at the surface of a polyoxometalate, highlighting the ability of a polyoxovanadate-alkoxide cluster, [VO(OCH)], to function as a homogeneous model for reducible metal oxides. The removal of an oxide ion from [VO(OCH)] results in the formation of a reactive vanadium(III) cation within the multimetallic framework. Generation of [VO(OCH)] is confirmed by H NMR, infrared and electronic absorption spectroscopies, as well as electrospray ionization mass spectrometry. The consequences of oxygen atom removal on the electrochemical profile of the assembly are assessed, revealing that stabilization of the reduced cluster is achieved through delocalized electron density. The oxygen-atom vacancy permits activation of O, demonstrating the ability of polyoxovanadate-alkoxide clusters to serve as both structural and functional models of reducible metal oxides.

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“…They work by forming acylase complexes with penicillin-binding proteins (PBPs), destroying the integrity of the cell wall and eventually leading to cell lysis, thereby inhibiting transpeptidase activity [ 21 ]. However, β-lactam antibiotics exert a strong selective pressure on bacteria, driving their evolution to produce a suite of enzymes capable of effectively degrading or inactivating β-lactam antibiotics, consequently endowing bacteria with increasing tolerance [ 22 , 23 ]. Therefore, β-lactamase inhibitors need to be urgently developed [ 19 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Spermacoce alata Aubl. Essential Oil: Chemical Composition, In Vitro Antioxidant Activity, and Inhibitory Effects of Acetylcholinesterase, α-Glucosidase and β-Lactamase

Zhu,

et al. 2024

Molecules

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Spermacoce alata Aubl. is widely available in the market as traditional Chinese medicine and animal feed, due to its properties of clearing heat and treating malaria and its high-protein and crude fiber content. In this study, the essential oil of S. alata was obtained through hydrodistillation. GC–MS and GC–FID methods were used to identify the chemical components and their relative abundance. Furthermore, the antioxidant capacity was measured using DPPH, ABTS, and FRAP assays, and the inhibitory effects of acetylcholinesterase, α-glucosidase, and β-lactamase were also evaluated. A total of 67 compounds were identified, with the major constituents being palmitic acid (30.74%), linoleic acid (16.13%), and phenylheptatriyne (8.07%). The essential oil exhibited moderate antioxidant activity against DPPH (IC50 > 10 mg/mL), while the IC50 value for the ABTS assay was 3.84 ± 2.12 mg/mL and the FRAP assay value was 87.22 ± 12.22 µM/g. Additionally, the essential oil showed moderate anti-acetylcholinesterase activity (IC50 = 286.0 ± 79.04 μg/mL), significant anti-α-glucosidase activity (IC50 = 174.7 ± 13.12 μg/mL), and potent anti-β-lactamase activity (IC50 = 37.56 ± 3.48 μg/mL). The results suggest that S. alata has the potential for application in pharmacology, warranting further exploration and investigation.

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Alkylidene Oxapenem β-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges

Cited by 6 publications

References 18 publications

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

Oxygen-Atom Vacancy Formation at Polyoxovanadate Clusters: Homogeneous Models for Reducible Metal Oxides

Spermacoce alata Aubl. Essential Oil: Chemical Composition, In Vitro Antioxidant Activity, and Inhibitory Effects of Acetylcholinesterase, α-Glucosidase and β-Lactamase

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