Design and synthesis of a library of C8-substituted sulfamidoadenosines to probe bacterial permeability.

Gram-negative bacteria pose a major challenge in antibiotic drug discovery because their cell envelope presents a permeability barrier that affords high intrinsic resistance to small-molecule drugs. The identification of correlations between chemical structure and Gram-negative permeability would thus enable development of predictive tools to facilitate antibiotic discovery. Toward this end, have advanced a library design paradigm in which various chemical scaffolds are functionalized at different regioisomeric positions using a uniform reagent set. This design enables decoupling of scaffold, regiochemistry, and substituent effects upon Gram-negative permeability of these molecules. Building upon our recent synthesis of a library of C2-substituted sulfamidoadenosines, we have now developed an efficient synthetic route to an analogous library of regioisomeric C8-substituted congeners. The C8 library samples a region of antibiotic-relevant chemical space that is similar to that addressed by the C2 library, but distinct from that sampled by a library of analogously substituted oxazolidinones. Selected molecules were tested for accumulation in Escherichia coli in a pilot analysis, setting the stage for full comparative evaluation of these libraries in the future.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B.S.S. is a former employee of Merck Sharpe & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. D.S.T. has received in-kind research support from Merck Sharpe & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA as a collaborating institution on this project and, in the last 3 years, has held equity interests in Merck & Co., Inc., Rahway, NJ, USA.
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