Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1

Chen, Allie Y.; Thomas, Pei W.; Stewart, Alesha C.; Bergstrom, Alexander; Cheng, Zishuo; Miller, Callie; Bethel, Christopher R.; Marshall, Steven H.; Credille, Cy V.; Riley, Christopher L.; Page, Richard C.; Bonomo, Robert A.; Crowder, Michael W.; Tierney, David L.; Fast, Walter; Cohen, Seth M.

doi:10.1021/acs.jmedchem.7b00407

Cited by 131 publications

(161 citation statements)

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“…[28] Also during the time of this study,as tructure of 2 in complex with IMP-1 (PDB ID:5 HH4) was reported. [28] Also during the time of this study,as tructure of 2 in complex with IMP-1 (PDB ID:5 HH4) was reported.…”

Section: Uv/vis Spectroscopymentioning

confidence: 95%

“…[22,47] The inclusion of captopril to the sample resultsi nl arge changes in the ligand field transitions, and an increase in the LMCT band. [28] Incubation of CoCo-NDM-1 with compounds 1-4 and DPAresulted in ar eductiono fa bsorbance at 500-650nm( Figure 4), which indicates that Co II is being removed from the active site to varying degrees.C ompound 2 appears to remove the most Co II ,followed by compound 1,DPA, 3,and then 4.The findings with CoCo-NDM-1 are wholly consistent with the equilibrium dialysis results. [48] Incubation of CoCo-NDM-1 with EDTAr esulted in as ignificant decrease of the LMCT and ligand field peaks, indicating that EDTA strips the metal from NDM-1.…”

Section: Uv/vis Spectroscopymentioning

confidence: 97%

“…[28,43] LowerI C 50 values for fluorocillin relative to meropenem were expected due to using as maller [S]/K M ratio in thesee xperiments. An alternative substrate, fluorocillin (K M,NDM-1 = 460 nm), was used to increase assay sensitivity.…”

Section: Inhibition Assaysmentioning

confidence: 99%

“…[28] The spectrum of CoCo-NDM-1 shows an intense peak between 320-350 nm, which has been assigned to ac ysteine-to-Co II ligand-to-metal charget ransfer (LMCT) band,a nd multiple peaks between 500-650nm, which have been assignedt oC o II ligand field bands (Figure4). [28] The spectrum of CoCo-NDM-1 shows an intense peak between 320-350 nm, which has been assigned to ac ysteine-to-Co II ligand-to-metal charget ransfer (LMCT) band,a nd multiple peaks between 500-650nm, which have been assignedt oC o II ligand field bands (Figure4).…”

Section: Uv/vis Spectroscopymentioning

confidence: 99%

“…The flexible active site of NDM-1, the diversity of relatedM BLs, al ack of understanding for inhibition mechanisms, and misinterpretation of structural data have all contributed to delayedi nhibitor development. [28] Derivatization of DPAw as performed to obtain 4-(3aminophenyl)pyridine-2,6-dicarboxylic acid ( Figure 1) as a highly selective inhibitor for NDM-1 (IMP-1 and VIM-2) that inhibits by forming as table NDM-1:Zn II :inhibitor ternary complex. [25,26] In line with this, our lab previouslyu sed af ragment-based drugd iscovery( FBDD) approacht oi dentify dipicolinica cid (DPA) as al ead metalbinding pharmacophore (MBP) for NDM-1i nhibitor development.…”

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Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

et al. 2019

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New Delhi metallo‐β‐lactamase‐1 (NDM‐1) poses an immediate threat to our most effective and widely prescribed drugs, the β‐lactam‐containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM‐1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the ZnII ions in the active site of NDM‐1 make up a large portion of the >500 inhibitors reported to date. New and structurally diverse scaffolds for inhibitor development are needed urgently. Herein we report the isosteric replacement of one carboxylate group of dipicolinic acid (DPA) to obtain DPA isosteres with good inhibitory activity against NDM‐1 (and related metallo‐β‐lactamases, IMP‐1 and VIM‐2). It was determined that the choice of carboxylate isostere influences both the potency of NDM‐1 inhibition and the mechanism of action. Additionally, we show that an isostere with a metal‐stripping mechanism can be re‐engineered into an inhibitor that favors ternary complex formation. This work provides a roadmap for future isosteric replacement of routinely used metal binding motifs (i.e., carboxylic acids) for the generation of new entities in NDM‐1 inhibitor design and development.

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Section: Uv/vis Spectroscopymentioning

confidence: 95%

Section: Uv/vis Spectroscopymentioning

confidence: 97%

Section: Inhibition Assaysmentioning

confidence: 99%

Section: Uv/vis Spectroscopymentioning

confidence: 99%

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Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

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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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Synthetic Studies with Bacitracin A and Preparation of Analogues Containing Alternative Zinc Binding Groups

et al. 2022

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The growing threat of drug-resistant bacteria is a global concern, highlighting the urgent need for new antibiotics and antibacterial strategies. In this light, practical synthetic access to natural product antibiotics can provide important structureactivity insights while also opening avenues for the development of novel analogues with improved properties. To this end, we report an optimised synthetic route for the preparation of the clinically used macrocyclic peptide antibiotic bacitracin. Our combined solid-and solution-phase approach addresses the problematic, and previously unreported, formation of undesired epimers associated with the stereochemically fragile N-terminal thiazoline moiety. A number of bacitracin analogues were also prepared wherein the thiazoline motif was replaced by other known zinc-binding moieties and their antibacterial activities evaluated.[a] N. Buijs, H.

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Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1

Cited by 131 publications

References 65 publications

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

Medicinal Chemistry of β‐Lactam Antibiotics

Synthetic Studies with Bacitracin A and Preparation of Analogues Containing Alternative Zinc Binding Groups

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