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The increasing prevalence of antibiotic resistance among bacterial pathogens is a serious threat to global health. A particular problem is the spread of multidrug-resistant Gram-negative bacterial pathogens. In this regard, the increased prevalence of carbapenemase enzymes such as the NDM, OXA-48 and KPC -lactamases has reduced the efficacy of -lactam antibiotics. In collaboration with Martin Matzuk and the Center for Drug Discovery at BCM, we are using a DNA-encoded chemical library (DECL) approach to discovery small molecule inhibitors of carbapenemases.

The DECL approach involves the creation of libraries of drug-like molecules covalently attached to a unique DNA barcode that enables identification of binders for a target in a pool of millions to billions of compounds. The conjugates are constructed in sequential cycles of chemical attachment of drug-like fragments (chemical building blocks) to a molecular scaffold concomitantly encoded through the ligation of a unique DNA barcode. The libraries can be screened against a tagged version of the protein target to identity molecules with high affinity, which are isolated though the pull-down of the tag from solution. Next-generation DNA sequencing allows the determination of the DNA barcode sequences isolated, and, thus, the structures of the high-affinity compounds. Synthesis of the compounds in the absence of the DNA tag and testing for binding and inhibition of the target proteins is used to validate the hit compounds.

We have recently used the DECL approach to discover novel inhibitors of the OXA-48 carbapenemase (Taylor et al., 2020). We are currently using DECL to discover inhibitors for the NDM and KPC carbapenemases as well as for the colistin-resistance enzyme, MCR-1.