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New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development

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New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development. / Seyfert, Carsten E; Müller, Alison V; Walsh, Danica J; Birkelbach, Joy; Kany, Andreas M; Porten, Christoph; Yuan, Biao; Krug, Daniel; Herrmann, Jennifer; Marlovits, Thomas C; Hirsch, Anna K H; Müller, Rolf.

In: J MED CHEM, Vol. 66, No. 23, 14.12.2023, p. 16330-16341.

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

Harvard

Seyfert, CE, Müller, AV, Walsh, DJ, Birkelbach, J, Kany, AM, Porten, C, Yuan, B, Krug, D, Herrmann, J, Marlovits, TC, Hirsch, AKH & Müller, R 2023, 'New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development', J MED CHEM, vol. 66, no. 23, pp. 16330-16341. https://doi.org/10.1021/acs.jmedchem.3c01660

APA

Seyfert, C. E., Müller, A. V., Walsh, D. J., Birkelbach, J., Kany, A. M., Porten, C., Yuan, B., Krug, D., Herrmann, J., Marlovits, T. C., Hirsch, A. K. H., & Müller, R. (2023). New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development. J MED CHEM, 66(23), 16330-16341. https://doi.org/10.1021/acs.jmedchem.3c01660

Vancouver

Seyfert CE, Müller AV, Walsh DJ, Birkelbach J, Kany AM, Porten C et al. New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development. J MED CHEM. 2023 Dec 14;66(23):16330-16341. https://doi.org/10.1021/acs.jmedchem.3c01660

Bibtex

@article{48afd8990821484a8e1bcbd03c49c074,
title = "New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development",
abstract = "Biosynthetic engineering of bicyclic darobactins, selectively sealing the lateral gate of the outer membrane protein BamA, leads to active analogues, which are up to 128-fold more potent against Gram-negative pathogens compared to native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising new antibiotic classes of the past decades. Here, we present a series of structure-driven biosynthetic modifications of our current frontrunner, darobactin 22 (D22), to investigate modifications at the understudied positions 2, 4, and 5 for their impact on bioactivity. Novel darobactins were found to be highly active against critical pathogens from the WHO priority list. Antibacterial activity data were corroborated by dissociation constants with BamA. The most active derivatives D22 and D69 were subjected to ADMET profiling, showing promising features. We further evaluated D22 and D69 for bioactivity against multidrug-resistant clinical isolates and found them to have strong activity.",
keywords = "Anti-Bacterial Agents/pharmacology, Microbial Sensitivity Tests, Phenylpropionates",
author = "Seyfert, {Carsten E} and M{\"u}ller, {Alison V} and Walsh, {Danica J} and Joy Birkelbach and Kany, {Andreas M} and Christoph Porten and Biao Yuan and Daniel Krug and Jennifer Herrmann and Marlovits, {Thomas C} and Hirsch, {Anna K H} and Rolf M{\"u}ller",
year = "2023",
month = dec,
day = "14",
doi = "10.1021/acs.jmedchem.3c01660",
language = "English",
volume = "66",
pages = "16330--16341",
journal = "J MED CHEM",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "23",

}

RIS

TY - JOUR

T1 - New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development

AU - Seyfert, Carsten E

AU - Müller, Alison V

AU - Walsh, Danica J

AU - Birkelbach, Joy

AU - Kany, Andreas M

AU - Porten, Christoph

AU - Yuan, Biao

AU - Krug, Daniel

AU - Herrmann, Jennifer

AU - Marlovits, Thomas C

AU - Hirsch, Anna K H

AU - Müller, Rolf

PY - 2023/12/14

Y1 - 2023/12/14

N2 - Biosynthetic engineering of bicyclic darobactins, selectively sealing the lateral gate of the outer membrane protein BamA, leads to active analogues, which are up to 128-fold more potent against Gram-negative pathogens compared to native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising new antibiotic classes of the past decades. Here, we present a series of structure-driven biosynthetic modifications of our current frontrunner, darobactin 22 (D22), to investigate modifications at the understudied positions 2, 4, and 5 for their impact on bioactivity. Novel darobactins were found to be highly active against critical pathogens from the WHO priority list. Antibacterial activity data were corroborated by dissociation constants with BamA. The most active derivatives D22 and D69 were subjected to ADMET profiling, showing promising features. We further evaluated D22 and D69 for bioactivity against multidrug-resistant clinical isolates and found them to have strong activity.

AB - Biosynthetic engineering of bicyclic darobactins, selectively sealing the lateral gate of the outer membrane protein BamA, leads to active analogues, which are up to 128-fold more potent against Gram-negative pathogens compared to native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising new antibiotic classes of the past decades. Here, we present a series of structure-driven biosynthetic modifications of our current frontrunner, darobactin 22 (D22), to investigate modifications at the understudied positions 2, 4, and 5 for their impact on bioactivity. Novel darobactins were found to be highly active against critical pathogens from the WHO priority list. Antibacterial activity data were corroborated by dissociation constants with BamA. The most active derivatives D22 and D69 were subjected to ADMET profiling, showing promising features. We further evaluated D22 and D69 for bioactivity against multidrug-resistant clinical isolates and found them to have strong activity.

KW - Anti-Bacterial Agents/pharmacology

KW - Microbial Sensitivity Tests

KW - Phenylpropionates

U2 - 10.1021/acs.jmedchem.3c01660

DO - 10.1021/acs.jmedchem.3c01660

M3 - SCORING: Journal article

C2 - 38093695

VL - 66

SP - 16330

EP - 16341

JO - J MED CHEM

JF - J MED CHEM

SN - 0022-2623

IS - 23

ER -