Discovery of an Effective Small-Molecule Allosteric Inhibitor of New Delhi Metallo-β-lactamase (NDM)

Thomas, Pei W.; Cho, Eun Jeong; Bethel, Christopher R.; Smisek, Thomas; Ahn, Yeong-Chan; Schroeder, John M.; Thomas, Charles Swain; Dalby, Kevin N.; Beckham, Josh T.; Crowder, Michael W.; Fast, Walter

doi:10.1021/acsinfecdis.1c00577

Cited by 9 publications

(8 citation statements)

References 64 publications

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“…Imbalanced Data and Data Preparation. We filtered 1003 "good" inhibitors (defined as having IC 50 < 10 μM), compiled on MBLInhibitors.com, and 44,012 from a previous HTS experiment 7 (defined as having >50% inhibition at 10 μM of the compound), leaving 538 and 43,366 compounds, respectively. After removing duplicate compounds, there were a total of 43,427 compounds in the combined data set.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…■ METHODS AND MATERIALS Data Collection. The initial chemical compound data set was composed of previously published chemical compounds obtained from MBLInhibitors.com 18 and compounds obtained from a high-throughput screening (HTS) experiment 7 (Figure 1a). The combined data set was filtered to remove any compounds deemed unusable due to lack of relevant data.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Traditionally, three approaches have been used to identify potential MBL inhibitors, including: (1) high-throughput screening (HTS) of large chemical libraries, (2) de novo molecular design, such as fragment-based drug discovery (FBDD) that utilizes known metal binding scaffolds and optimizes the compounds to bind tighter to or to exhibit different inhibition properties against different MBLs, , and (3) molecular docking, which identifies the “best” compounds (defined in many ways), matching three-dimensional geometrical shapes between the small molecules and the active site of the enzyme target(s). − Methods of drug discovery such as HTS and de novo molecule design are labor-intensive, costly, and time-consuming. In addition, the “accurate” docking of compounds into existing MBLs (crystal structures) requires initial assumptions of how the compound(s) bind (for example, which atoms coordinate to or bridge the Zn(II) ions) .…”

Section: Introductionmentioning

confidence: 99%

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Machine Learning Models Identify Inhibitors of New Delhi Metallo-β-lactamase

Cheng,

Aitha,

Thomas

et al. 2024

J. Chem. Inf. Model.

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The worldwide spread of the metallo-β-lactamases (MBL), especially New Delhi metallo-β-lactamase-1 (NDM-1), is threatening the efficacy of β-lactams, which are the most potent and prescribed class of antibiotics in the clinic. Currently, FDA-approved MBL inhibitors are lacking in the clinic even though many strategies have been used in inhibitor development, including quantitative high-throughput screening (qHTS), fragment-based drug discovery (FBDD), and molecular docking. Herein, a machine learningbased prediction tool is described, which was generated using results from HTS of a large chemical library and previously published inhibition data. The prediction tool was then used for virtual screening of the NIH Genesis library, which was subsequently screened using qHTS. A novel MBL inhibitor was identified and shown to lower minimum inhibitory concentrations (MICs) of Meropenem for a panel of E. coli and K. pneumoniae clinical isolates expressing NDM-1. The mechanism of inhibition of this novel scaffold was probed utilizing equilibrium dialyses with metal analyses, native state electrospray ionization mass spectrometry, UV−vis spectrophotometry, and molecular docking. The uncovered inhibitor, compound 72922413, was shown to be 9-hydroxy-3-[(5-hydroxy-1-oxa-9-azaspiro[5.5]undec-9-yl)carbonyl]-4Hpyrido[1,2-a]pyrimidin-4-one.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Machine Learning Models Identify Inhibitors of New Delhi Metallo-β-lactamase

Cheng,

Aitha,

Thomas

et al. 2024

J. Chem. Inf. Model.

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“…These novel inhibitor chemotypes have led to new combination therapies targeting β-lactam resistance and a better understanding of β-lactamase activity. (1 [105], 2 [106], 3 [107], 4 [108], Ixazomib [109], 5 [110], 6 [111], 7 [112], ZINC549719643 [89], 8 [113], 9 [114], 10 [115], 11 [116], 12 [117], 13 [118], 14 [119], 15 [120], 16 [121], QPX7728 [122,123], 17 [124], 18 [125], 19 [126], 20 [127]).…”

Section: Novel β-Lactamase Inhibitor Scaffoldsmentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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“…Several other reports indicate metal chelators could be rapid and potent MBLIs of the NDM, VIM, and IMP variants. These include the nitrogen donor chelators, ZN148 [ 30 ], H 2 dpa [ 31 ] and 2-quinazolinone derivatives [ 32 ], the sulphonamide-oxygen chelators ANT2681 [ 33 ] and N -sulfamoylpyrrole-2-carboxylates [ 34 ] as well as the 1,2,4-triazole-3-thione compounds bearing 4-ethyl alkyl/aryl sulfide substituents [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors

et al. 2023

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Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

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Discovery of an Effective Small-Molecule Allosteric Inhibitor of New Delhi Metallo-β-lactamase (NDM)

Cited by 9 publications

References 64 publications

Machine Learning Models Identify Inhibitors of New Delhi Metallo-β-lactamase

Machine Learning Models Identify Inhibitors of New Delhi Metallo-β-lactamase

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors

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