Tetracycline resistance by antibiotic inactivation was first identified in commensal organisms but has since been reported in environmental and pathogenic microbes. Here, we identify and characterize an expanded pool of tet(X)-like genes in environmental and human commensal metagenomes via inactivation by antibiotic selection of metagenomic libraries. These genes formed two distinct clades according to habitat of origin, and resistance phenotypes were similarly correlated. Each gene isolated from the human gut encodes resistance to all tetracyclines tested, including eravacycline and omadacycline. We report a biochemical and structural characterization of one enzyme, Tet(X7). Further, we identify Tet(X7) in a clinical Pseudomonas aeruginosa isolate and demonstrate its contribution to tetracycline resistance. Lastly, we show anhydrotetracycline and semi-synthetic analogues inhibit Tet(X7) to prevent enzymatic tetracycline degradation and increase tetracycline efficacy against strains expressing tet(X7). This work improves our understanding of resistance by tetracyclineinactivation and provides the foundation for an inhibition-based strategy for countering resistance.
Tetracyclines have been foundational antibacterial agents for more than 70 years. Renewed interest in tetracycline antibiotics is being driven by advancements in tetracycline synthesis and strategic scaffold modifications designed to overcome established clinical resistance mechanisms including efflux and ribosome protection. Emerging new resistance mechanisms, including enzymatic antibiotic inactivation, threaten recent progress on bringing these next-generation tetracyclines to the clinic. Here we review the current state of knowledge on the structure, mechanism, and inhibition of tetracycline-inactivating enzymes.
The synthesis and biological evaluation of semisynthetic anhydrotetracycline analogues as small molecule inhibitors of tetracycline-inactivating enzymes are reported. Inhibitor potency was found to vary as a function of enzyme (major) and substrate-inhibitor pair (minor), and anhydrotetracycline analog stability to enzymatic and non-enzymatic degradation in solution contributes to their ability to rescue tetracycline activity in whole cell E. coli expressing tetracycline destructase enzymes. Taken collectively, these results provide the framework for the *
Recent advances in phosphate tether-mediated natural product synthesis are reviewed. Synthetic approaches toward dolabelide C, (-)-salicylihalimide A, (-)-tetrahydrolipstatin, and (+)-strictifolione are included. In addition, current efforts in method development are briefly reviewed, including a detailed study on the effect of stereochemical complexity on the phosphate-mediated, diastereoselective ring-closing metathesis reaction and recent advances in multi-reaction, one-pot sequential processes mediated by the phosphate tether. Overall, this review seeks to highlight the utility of phosphate triesters to serve as multifunctional tethers with protecting group and latent leaving group characteristics and the ability to orchestrate multiple, orthogonal reaction pathways to allow for the facile synthesis of complex, bioactive small molecules and their analogs.
An array of examples of diastereoselective, phosphate tether-mediated ring-closing metathesis reactions, which highlight the importance of product ring size and substrate stereochemical compatibility, as well as complexity, is reported. Studies focus primarily on the formation of bicyclo[n.3.1]phosphates, involving the coupling of C2-symmetric dienediol subunits with a variety of simple, as well as complex alcohol cross-partners.
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