Broadening the spectrum of oxazolidinone antibacterial drugs to encompass Gram-negative bacteria

Antimicrobial resistance (AMR) – particularly in Gram-negative (G-VE) bacteria – poses a global health threat, and new antimicrobial therapies are required to address the problem. However, the discovery and development of drugs that can target G-VE bacteria represents a major challenge. G-VE bacteria are characterized by an impermeable outer membrane (OM) and extensive multidrug resistant efflux pumps that work together to diminish intracellular drug accumulation, rendering them intrinsically resistant to many antibacterial drug classes. The importance of these mechanisms in AMR can be seen in the fact that many anti-Gram-positive (G+VE) antibacterial drugs actually demonstrate useful G-VE activity if they are enabled to penetrate the OM barrier and/or avoid efflux. Oxazolidinones are a class of antibacterial drugs whose clinical use is currently limited to the treatment of G+VE infections. In this project, structural modifications were applied to the oxazolidinone scaffold with the aim of improving G-VE accumulation and antibacterial activity. Several rational design strategies were adopted to achieve this goal. Consecutive rounds of investigating suitable attachment points and compatible structural motifs led to the identification of compound 3.20 that demonstrated G-VE activity with an MIC of 32 μg/mL against E. coli compared with an MIC of 256 μg/mL by the oxazolidinone reference compound, linezolid. Further optimization of 3.20 culminated in the development of the more potent analogue (4.16) with an MIC of 8 μg/mL against E. coli. The results demonstrate the potential of rationally modifying existing G+VE antibacterial drugs to evolve new compounds with broader spectrum of antibacterial activity encompassing G-VE bacteria, an approach that could help to tackle the AMR crisis.