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Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity

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Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity. / Mielniczuk, Sebastian; Hoff, Katharina; Baselious, Fady; Li, Yunqi; Haupenthal, Jörg; Kany, Andreas M; Riedner, Maria; Rohde, Holger; Rox, Katharina; Hirsch, Anna K H; Krimm, Isabelle; Sippl, Wolfgang; Holl, Ralph.

In: J MED CHEM, Vol. 67, No. 19, 10.10.2024, p. 17363-17391.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Mielniczuk, S, Hoff, K, Baselious, F, Li, Y, Haupenthal, J, Kany, AM, Riedner, M, Rohde, H, Rox, K, Hirsch, AKH, Krimm, I, Sippl, W & Holl, R 2024, 'Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity', J MED CHEM, vol. 67, no. 19, pp. 17363-17391. https://doi.org/10.1021/acs.jmedchem.4c01262

APA

Mielniczuk, S., Hoff, K., Baselious, F., Li, Y., Haupenthal, J., Kany, A. M., Riedner, M., Rohde, H., Rox, K., Hirsch, A. K. H., Krimm, I., Sippl, W., & Holl, R. (2024). Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity. J MED CHEM, 67(19), 17363-17391. https://doi.org/10.1021/acs.jmedchem.4c01262

Vancouver

Mielniczuk S, Hoff K, Baselious F, Li Y, Haupenthal J, Kany AM et al. Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity. J MED CHEM. 2024 Oct 10;67(19):17363-17391. https://doi.org/10.1021/acs.jmedchem.4c01262

Bibtex

@article{99e527f68a684703a46a1f4575e4ef68,
title = "Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity",
abstract = "In a fragment-based approach using NMR spectroscopy, benzyloxyacetohydroxamic acid-derived inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the uridine diphosphate-binding site of the enzyme were developed. By appending privileged fragments via a suitable linker, potent LpxC inhibitors with promising antibacterial activities could be obtained, like the one-digit nanomolar LpxC inhibitor (S)-13j [Ki (EcLpxC C63A) = 9.5 nM; Ki (PaLpxC): 5.6 nM]. To rationalize the observed structure-activity relationships, molecular docking and molecular dynamics studies were performed. Initial in vitro absorption-distribution-metabolism-excretion-toxicity (ADMET) studies of the most potent compounds have paved the way for multiparameter optimization of our newly developed isoserine-based amides.",
keywords = "Amidohydrolases/antagonists & inhibitors, Structure-Activity Relationship, Anti-Bacterial Agents/pharmacology, Molecular Docking Simulation, Enzyme Inhibitors/pharmacology, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Hydroxamic Acids/chemistry, Humans, Animals",
author = "Sebastian Mielniczuk and Katharina Hoff and Fady Baselious and Yunqi Li and J{\"o}rg Haupenthal and Kany, {Andreas M} and Maria Riedner and Holger Rohde and Katharina Rox and Hirsch, {Anna K H} and Isabelle Krimm and Wolfgang Sippl and Ralph Holl",
year = "2024",
month = oct,
day = "10",
doi = "10.1021/acs.jmedchem.4c01262",
language = "English",
volume = "67",
pages = "17363--17391",
journal = "J MED CHEM",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "19",

}

RIS

TY - JOUR

T1 - Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity

AU - Mielniczuk, Sebastian

AU - Hoff, Katharina

AU - Baselious, Fady

AU - Li, Yunqi

AU - Haupenthal, Jörg

AU - Kany, Andreas M

AU - Riedner, Maria

AU - Rohde, Holger

AU - Rox, Katharina

AU - Hirsch, Anna K H

AU - Krimm, Isabelle

AU - Sippl, Wolfgang

AU - Holl, Ralph

PY - 2024/10/10

Y1 - 2024/10/10

N2 - In a fragment-based approach using NMR spectroscopy, benzyloxyacetohydroxamic acid-derived inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the uridine diphosphate-binding site of the enzyme were developed. By appending privileged fragments via a suitable linker, potent LpxC inhibitors with promising antibacterial activities could be obtained, like the one-digit nanomolar LpxC inhibitor (S)-13j [Ki (EcLpxC C63A) = 9.5 nM; Ki (PaLpxC): 5.6 nM]. To rationalize the observed structure-activity relationships, molecular docking and molecular dynamics studies were performed. Initial in vitro absorption-distribution-metabolism-excretion-toxicity (ADMET) studies of the most potent compounds have paved the way for multiparameter optimization of our newly developed isoserine-based amides.

AB - In a fragment-based approach using NMR spectroscopy, benzyloxyacetohydroxamic acid-derived inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the uridine diphosphate-binding site of the enzyme were developed. By appending privileged fragments via a suitable linker, potent LpxC inhibitors with promising antibacterial activities could be obtained, like the one-digit nanomolar LpxC inhibitor (S)-13j [Ki (EcLpxC C63A) = 9.5 nM; Ki (PaLpxC): 5.6 nM]. To rationalize the observed structure-activity relationships, molecular docking and molecular dynamics studies were performed. Initial in vitro absorption-distribution-metabolism-excretion-toxicity (ADMET) studies of the most potent compounds have paved the way for multiparameter optimization of our newly developed isoserine-based amides.

KW - Amidohydrolases/antagonists & inhibitors

KW - Structure-Activity Relationship

KW - Anti-Bacterial Agents/pharmacology

KW - Molecular Docking Simulation

KW - Enzyme Inhibitors/pharmacology

KW - Microbial Sensitivity Tests

KW - Molecular Dynamics Simulation

KW - Hydroxamic Acids/chemistry

KW - Humans

KW - Animals

U2 - 10.1021/acs.jmedchem.4c01262

DO - 10.1021/acs.jmedchem.4c01262

M3 - SCORING: Journal article

C2 - 39303295

VL - 67

SP - 17363

EP - 17391

JO - J MED CHEM

JF - J MED CHEM

SN - 0022-2623

IS - 19

ER -