SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

Leiris, Simon; Coelho, Alicia; Castandet, Jérôme; Bayet, Maëlle; Lozano, Clarisse; Bougnon, Juliette; Bousquet, Justine; Everett, Martin; Lemonnier, Marguerite; Sprynski, Nicolas; Zalacaı́n, Magdalena; Pallin, T. David; Cramp, Michael C.; Jennings, Neil; Raphy, Gilles; Jones, Mark; Pattipati, Ramesh; Shankar, Battu; Sivasubrahmanyam, Relangi; Soodhagani, Ashok Kumar; Juventhala, Ramakrishna Reddy; Pottabathini, Narender; Srinivasu, Pavuluri; Benvenuti, Manuela; Pozzi, Cecilia; Mangani, Stefano; Luca, Filomena De; Cerboni, Giulia; Docquier, Jean Denis; Davies, David T.

doi:10.1021/acsinfecdis.8b00246

Cited by 49 publications

(44 citation statements)

References 23 publications

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“…S9 ). The most important residues on loop L10 are Arg228/185 and Asn233/190 in VIM-2 41 , Lys224/211 and the same Asn233/210 in NDM-1. Interestingly, Lys224/211 is conserved in all subclass B1 representatives, apart from the VIM variants.…”

Section: Resultsmentioning

confidence: 99%

Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases

Spyrakis

Santucci

Maso

et al. 2020

Sci Rep

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Bacteria are known to evade β - lactam antibiotic action by producing β-lactamases (BLs), including carbapenemases, which are able to hydrolyze nearly all available β-lactams. The production of BLs represents one of the best known and most targeted mechanisms of resistance in bacteria. We have performed the parallel screening of commercially available compounds against a panel of clinically relevant BLs: class A CTX-M-15 and KPC-2, subclass B1 NDM-1 and VIM-2 MBLs, and the class C P. aeruginosa AmpC. The results show that all BLs prefer scaffolds having electron pair donors: KPC-2 is preferentially inhibited by sulfonamide and tetrazole-based derivatives, NDM-1 by compounds bearing a thiol, a thiosemicarbazide or thiosemicarbazone moiety, while VIM-2 by triazole-containing molecules. Few broad-spectrum BLs inhibitors were identified; among these, compound 40 potentiates imipenem activity against an NDM-1-producing E. coli clinical strain. The binary complexes of the two most promising compounds binding NDM-1 and VIM-2 were obtained at high resolution, providing strong insights to improve molecular docking simulations, especially regarding the interaction of MBLs with inhibitors.

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Section: Resultsmentioning

confidence: 99%

Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases

Spyrakis

Santucci

Maso

et al. 2020

Sci Rep

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“…However, none of them has been clinically approved [ 8 , 15 ]. These are natural plant-based compounds [ 16 , 17 ], synthetic low molecular weight inhibitors [ 10 , 18 , 19 , 20 , 21 , 22 ], β-lactams [ 23 , 24 , 25 , 26 ], amino acid derivatives and peptides [ 27 ]. Boron-based inhibitors attract special attention [ 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.

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“…Despite intense research efforts, only one compound has reached clinical development (i.e., VNRX-5133), a pan-spectrum inhibitor active on both SBLs and MBLs with a cyclic boronate structure [ 24 , 25 , 26 , 27 ]. A few other lead compounds that could efficiently restore bacterial sensitivity to carbapenems, including in in vivo infection models, were also reported [ 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

“…Biomolecules 2020, 10, x 3 of 18 other lead compounds that could efficiently restore bacterial sensitivity to carbapenems, including in in vivo infection models, were also reported [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

4-(N-Alkyl- and -Acyl-amino)-1,2,4-triazole-3-thione Analogs as Metallo-β-Lactamase Inhibitors: Impact of 4-Linker on Potency and Spectrum of Inhibition

et al. 2020

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To fight the increasingly worrying bacterial resistance to antibiotics, the discovery and development of new therapeutics is urgently needed. Here, we report on a new series of 1,2,4-triazole-3-thione compounds as inhibitors of metallo-β-lactamases (MBLs), which represent major resistance determinants to β-lactams, and especially carbapenems, in Gram-negative bacteria. These molecules are stable analogs of 4-amino-1,2,4-triazole-derived Schiff bases, where the hydrazone-like bond has been reduced (hydrazine series) or the 4-amino group has been acylated (hydrazide series); the synthesis and physicochemical properties thereof are described. The inhibitory potency was determined on the most clinically relevant acquired MBLs (IMP-, VIM-, and NDM-types subclass B1 MBLs). When compared with the previously reported hydrazone series, hydrazine but not hydrazide analogs showed similarly potent inhibitory activity on VIM-type enzymes, especially VIM-2 and VIM-4, with Ki values in the micromolar to submicromolar range. One of these showed broad-spectrum inhibition as it also significantly inhibited VIM-1 and NDM-1. Restoration of β-lactam activity in microbiological assays was observed for one selected compound. Finally, the binding to the VIM-2 active site was evaluated by isothermal titration calorimetry and a modeling study explored the effect of the linker structure on the mode of binding with this MBL.

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SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

Cited by 49 publications

References 23 publications

Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases

Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

4-(N-Alkyl- and -Acyl-amino)-1,2,4-triazole-3-thione Analogs as Metallo-β-Lactamase Inhibitors: Impact of 4-Linker on Potency and Spectrum of Inhibition

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