This strategy allows for highly selective killing and minimizes the potential for mitotoxicity.

In this study, we demonstrate that it is possible to hijack intrinsic resistance mechanisms in Mycobacterium abscessus by utilizing the aminoglycoside resistance protein Eis2 to activate florfenicol amine in a prodrug approach.

Collectively, it contributes to our overall understanding of Gram-negative permeability and demonstrates the applicability of target engagement as a metric for guiding SAR in antibiotic development.

This work increases our knowledge of the SAR of pterin-site inhibitors of DHPS, an important antifolate drug target, identifies 4367 as a validated cell-active DHPS inhibitor, and demonstrates the successful application of rapid HiBiT CETSA for drug discovery in Gram-negative bacteria.

This orthogonal assay platform was used to reevaluate the SAR of our Legacy pyrimido-pyridazine compound series against E. coli DHPS and to facilitate the design of an exploratory series of compounds with improved permeability, yielding a new lead with high cellular target engagement.

The results, when combined with surface plasmon resonance to measure target affinity and LC-MS/MS-based accumulation measurements, provide tractable medicinal chemistry data for lead development.

Key to this study is the development of a HiBiT thermal stability whole-cell target engagement assay that compares drug-induced thermal stabilization of the target in whole cells with that in cellular lysate.

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