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, Jahrgang 66, Nr. 23, 14.12.2023, S. 16330-16341.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -