Broadening the Spectrum of Antibacterial Agents to Tackle Multidrug-Resistant Gram-Negative Pathogens

Antimicrobial resistance is one of the greatest threats to human health in the 21st century: particularly resistance amongst Gram-negative bacteria. The work presented herein aims to identify new agents that target drug-resistant Gram-negative pathogens such as E. coli, through the rational modification of the oxazolidinone class of antibiotics. This class, exemplified by linezolid, is well validated for treating Gram-positive derived infections, but lacks clinically-useful activity against Gram-negative bacteria. An integrated approach encompassing structure-based drug design, organic synthesis and microbiology has been used to design, synthesise and biologically evaluate 33 oxazolidinone variants.

A two-part strategy to potentiating oxazolidinone derivatives against E. coli was taken which involved improving predicted target-binding and enhancing the rate of compound ingress into the E. coli bacterium. It was hypothesised that oxazolidinones demonstrating substantial increases in either of these areas may minimise the detrimental impact on antibacterial activity caused by the efflux transporter AcrAB-TolC in E. coli. A structure-guided approach using in silico docking methods did not produce oxazolidinone derivatives with improved antibacterial activity against E. coli in this study. Attempts to increase E. coli activity by equipping compound libraries with ionisable nitrogen moieties whilst retaining a ribosomal-binding moiety at the C-5 oxazolidinone position proved to be a more successful strategy. A linezolid variant 10 featuring a piperazine in replacement for a morpholine ring, demonstrated an 8-fold increase in anti-E. coli activity over linezolid. Two compounds from a class termed ‘bis-oxazolidinones’, 69 and 72, exhibited on-target increases in anti-E. coli activity by 4- and 8 to 16-fold respectively, when compared to linezolid. Therefore, these findings demonstrate that it is possible to improve the anti-Gram-negative activity of the oxazolidinone class to encompass E. coli.