LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents

Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, <b>23j</b>, showed a low efflux ratio, nanomolar potencies against <i>E. coli</i> LpxC enzyme, and excellent antibacterial activity against <i>E. coli</i> and <i>K. pneumoniae</i>. Computational docking was used to predict the interaction between <b>23j</b> and <i>E. coli</i> LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors

Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC₅₀ > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and <i>Staphylococcus aureus</i> gyrase (IC₅₀ = 1.02 μM) and topo IV (IC₅₀ = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED₅₀) at less than 2.5 mg/kg doses in a <i>S. aureus</i> murine infection model. A cocrystal structure of AM8191 bound to <i>S. aureus</i> DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker