Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering

TY - JOUR

T1 - Darobactins Exhibiting Superior Antibiotic Activity by Cryo-EM Structure Guided Biosynthetic Engineering

AU - Seyfert, Carsten E

AU - Porten, Christoph

AU - Yuan, Biao

AU - Deckarm, Selina

AU - Panter, Fabian

AU - Bader, Chantal

AU - Coetzee, Janetta

AU - Deschner, Felix

AU - Tehrani, Kamaleddin

AU - Higgins, Paul G

AU - Seifert, Harald

AU - Marlovits, Thomas

AU - Herrmann, Jennifer

AU - Müller, Rolf

N1 - © 2022 Wiley-VCH GmbH.

PY - 2023/1/9

Y1 - 2023/1/9

N2 - Over recent decades, the pipeline of antibiotics acting against Gram-negative bacteria is running dry, as most discovered candidate antibiotics suffer from insufficient potency, pharmacokinetic properties, or toxicity. The darobactins, a promising new small peptide class of drug candidates, bind to novel antibiotic target BamA, an outer membrane protein. Previously, we reported that biosynthetic engineering in a heterologous host generated novel darobactins with enhanced antibacterial activity. Here we utilize an optimized purification method and present cryo-EM structures of the Bam complex with darobactin 9 (D9), which served as a blueprint for the biotechnological generation of twenty new darobactins including halogenated analogs. The newly engineered darobactin 22 binds more tightly to BamA and outperforms the favorable activity profile of D9 against clinically relevant pathogens such as carbapenem-resistant Acinetobacter baumannii up to 32-fold, without observing toxic effects.

AB - Over recent decades, the pipeline of antibiotics acting against Gram-negative bacteria is running dry, as most discovered candidate antibiotics suffer from insufficient potency, pharmacokinetic properties, or toxicity. The darobactins, a promising new small peptide class of drug candidates, bind to novel antibiotic target BamA, an outer membrane protein. Previously, we reported that biosynthetic engineering in a heterologous host generated novel darobactins with enhanced antibacterial activity. Here we utilize an optimized purification method and present cryo-EM structures of the Bam complex with darobactin 9 (D9), which served as a blueprint for the biotechnological generation of twenty new darobactins including halogenated analogs. The newly engineered darobactin 22 binds more tightly to BamA and outperforms the favorable activity profile of D9 against clinically relevant pathogens such as carbapenem-resistant Acinetobacter baumannii up to 32-fold, without observing toxic effects.

U2 - 10.1002/anie.202214094

DO - 10.1002/anie.202214094

M3 - SCORING: Journal article

C2 - 36308277

VL - 62

SP - e202214094

JO - ANGEW CHEM INT EDIT

JF - ANGEW CHEM INT EDIT

SN - 1433-7851

IS - 2

ER -