Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

Brem, Jürgen; Cain, Ricky; Cahill, Samuel T.; McDonough, M.A.; Clifton, I.J.; Jiménez-Castellanos, Juan-Carlos; Avison, Matthew B.; Spencer, James; Fishwick, Colin W. G.; Schofield, Christopher J.

doi:10.1038/ncomms12406

Cited by 210 publications

(307 citation statements)

References 40 publications

(65 reference statements)

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“…Consistent with our previous work (21), cyclic boronate 2 was observed to be a more potent inhibitor of the isolated MBLs than cyclic boronate 1. Since potency against different types of MBLs is a highly desirable characteristic in the design of MBL/SBL dual inhibitors, cyclic boronate 2 (10 μg/ml) was thus tested in combination with a number of β-lactams against a variety of Gram-negative clinical isolates known to produce multiple β-lactamases.…”

Section: Resultssupporting

confidence: 92%

“…To investigate the extent to which cyclic boronates inhibit class C β-lactamases as well as the important class A ESBL and class D carbapenemase targets, we used a fluorogenic assay (22) to screen the cyclic boronates, which we have found to inhibit other β-lactamases (21), against them. The β-lactamases used for screening included TEM-1 and CTX-M-15 (class A), the metallo-β-lactamase (MBL) from Bacillus cereus (BcII), Verona integron-encoded metallo-β-lactamase 1 (VIM-1) (class B), AmpC from P.…”

Section: Resultsmentioning

confidence: 99%

“…1). We have recently reported that cyclic boronates can inhibit representatives of class A, B, and D β-lactamases (21). Cyclic boronates act as analogues of the first tetrahedral intermediate that is common to both SBLs and MBLs (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Cyclic Boronates Inhibit All Classes of β-Lactamases

Cahill

Cain

Wang

et al. 2017

Antimicrob Agents Chemother

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105

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ABSTRACTβ-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of “dual-action” inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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Cyclic Boronates Inhibit All Classes of β-Lactamases

Cahill

Cain

Wang

et al. 2017

Antimicrob Agents Chemother

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105

158

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“…The structure implies substrate binding includes important interactions of the substrate carboxylate with Zn2 and the adjacent Lys219, as observed for hydrolyzed β‐lactams13 (Figure S7 in the Supporting Information) and β‐lactam analogues15 (Figure S9), as well as interactions with hydrophobic elements around the active site (Figure 4). The structure supports the involvement of these interactions in binding intact β‐lactam substrates, and, thus, in the formation of early‐stage complexes in catalysis.…”

mentioning

confidence: 86%

“…As such, it is proposed that binding of an intact β‐lactam triggers dissociation of Wat1 from Zn2 to generate a ”terminal“ hydroxide nucleophile on Zn1. The tetrahedral species formed by reaction of Wat1 with the β‐lactam carbonyl is stabilized by Zn1 binding, as supported by structural analysis of MBLs complexed with cyclic boronates, which are tetrahedral intermediate analogues (Figure S9 in the Supporting Information) 15. In the hydrated cyclobutanone, the C6 oxygen atoms are likely protonated, possibly reducing affinity for Zn1 and instead favoring interaction with Wat1.…”

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confidence: 89%

Cyclobutanone Mimics of Intermediates in Metallo‐β‐Lactamase Catalysis

Abboud

Kosmopoulou

Krismanich

et al. 2018

Chemistry A European J

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The most important resistance mechanism to β‐lactam antibiotics involves hydrolysis by two β‐lactamase categories: the nucleophilic serine and the metallo‐β‐lactamases (SBLs and MBLs, respectively). Cyclobutanones are hydrolytically stable β‐lactam analogues with potential to inhibit both SBLs and MBLs. We describe solution and crystallographic studies on the interaction of a cyclobutanone penem analogue with the clinically important MBL SPM‐1. NMR experiments using 19F‐labeled SPM‐1 imply the cyclobutanone binds to SPM‐1 with micromolar affinity. A crystal structure of the SPM‐1:cyclobutanone complex reveals binding of the hydrated cyclobutanone through interactions with one of the zinc ions, stabilisation of the hydrate by hydrogen bonding to zinc‐bound water, and hydrophobic contacts with aromatic residues. NMR analyses using a 13C‐labeled cyclobutanone support assignment of the bound species as the hydrated ketone. The results inform on how MBLs bind substrates and stabilize tetrahedral intermediates. They support further investigations on the use of transition‐state and/or intermediate analogues as inhibitors of all β‐lactamase classes.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

Cited by 210 publications

References 40 publications

Cyclic Boronates Inhibit All Classes of β-Lactamases

Cyclic Boronates Inhibit All Classes of β-Lactamases

Cyclobutanone Mimics of Intermediates in Metallo‐β‐Lactamase Catalysis

Medicinal Chemistry of β‐Lactam Antibiotics

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