Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

Reidl, Cory T.; Heath, Tahirah K; Darwish, Iman; Torrez, Rachel M; Moore, Maxwell J.; Gild, Elliot; Nocek, B.; Starus, Anna; Holz, Richard C.; Becker, Daniel P.

doi:10.3390/antibiotics9090595

Cited by 10 publications

(11 citation statements)

References 31 publications

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“…As expected, the new high-resolution X-ray structure of Nm DapE (PDB entry 5UEJ) shares many of the aspects of previously reported Hi DapE structures. Hi DapE and Nm DapE share a high degree of sequence homology of 55% with no sequence gaps and have the same active site architectures, including metal binding residues and substrate binding residues necessary for hydrolytic activity . Both are dimers with two domains in each chain (Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…HiDapE and NmDapE share a high degree of sequence homology of 55% with no sequence gaps and have the same active site architectures, including metal binding residues and substrate binding residues necessary for hydrolytic activity. 14 Both are dimers with two domains in each chain (Figure 2A). The catalytic domain is globular and contains two Zn 2+ ions and most of the catalytic residues.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…The requirement of this His residue explains the observed inactivity of a truncated, monomeric construct of DapE . The product-bound structure, aided by our product-bound transition state modeling (PBTSM) approach, , enabled further refinement of the proposed reaction mechanism of DapE that will facilitate inhibitor identification − for the discovery of new antibiotics that inhibit DapE.…”

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confidence: 99%

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Atomic-Resolution 1.3 Å Crystal Structure, Inhibition by Sulfate, and Molecular Dynamics of the Bacterial Enzyme DapE

et al. 2021

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We report the atomic-resolution (1.3 Å) X-ray crystal structure of an open conformation of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE, EC 3.5.1.18) from Neisseria meningitidis. This structure [Protein Data Bank (PDB) entry 5UEJ] contains two bound sulfate ions in the active site that mimic the binding of the terminal carboxylates of the N-succinyl-l,l-diaminopimelic acid (l,l-SDAP) substrate. We demonstrated inhibition of DapE by sulfate (IC50 = 13.8 ± 2.8 mM). Comparison with other DapE structures in the PDB demonstrates the flexibility of the interdomain connections of this protein. This high-resolution structure was then utilized as the starting point for targeted molecular dynamics experiments revealing the conformational change from the open form to the closed form that occurs when DapE binds l,l-SDAP and cleaves the amide bond. These simulations demonstrated closure from the open to the closed conformation, the change in RMS throughout the closure, and the independence in the movement of the two DapE subunits. This conformational change occurred in two phases with the catalytic domains moving toward the dimerization domains first, followed by a rotation of catalytic domains relative to the dimerization domains. Although there were no targeting forces, the substrate moved closer to the active site and bound more tightly during the closure event.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

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confidence: 99%

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Atomic-Resolution 1.3 Å Crystal Structure, Inhibition by Sulfate, and Molecular Dynamics of the Bacterial Enzyme DapE

et al. 2021

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“…The re‐exploration of targets of old natural products such as the sliding clamp of DNA polymerase, DnaN, either with new griselimycins obtained by total synthesis (Kling et al , 2015 ), or with small molecules discovered by iterative structure‐based synthesis (Monsarrat et al , 2021 ) or kinetic target‐guided synthesis (Mancini et al , 2020 ) also proved to be promising. The exploration of new targets such as energy‐coupling factor (ECF) transporters (Bousis et al , 2019 ) or dap E‐encoded N‐succinyl‐ l , l ‐diaminopimelic acid desuccinylase (DapE; Reidl et al , 2020 ), although challenging, opens the path to medicinal‐chemistry programs for the identification of novel antibiotic scaffolds with unprecedented modes of action.…”

Section: The Need For New Antibioticsmentioning

confidence: 99%

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

et al. 2022

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Antibacterial resistance is one of the greatest threats to human health. The development of new therapeutics against bacterial pathogens has slowed drastically since the approvals of the first antibiotics in the early and mid-20 th century. Most of the currently investigated drug leads are modifications of approved antibacterials, many of which are derived from natural products. In this review, we highlight the challenges, advancements and current standing of the clinical and preclinical antibacterial research pipeline. Additionally, we present novel strategies for rejuvenating the discovery process and advocate for renewed and enthusiastic investment in the antibacterial discovery pipeline.

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“…The research article by Reidl et al deals with N -acetyl-6-sulfonamide indoline derivatives as inhibitors of DapE [ 4 ]. This bacterial enzyme, which is indispensable for bacterial survival and pathogenesis but absent in humans, has been recently validated as a promising bacterial target for the design of antibiotics with a new mechanism of action.…”

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confidence: 99%