Tackling MDR Gram-negative infections by an MGB conjugation strategy

Urgent action is required to develop new and novel drugs to treat multi drug resistant bacterial infections. Without this, we risk slipping into a “post-antibiotic era” where a cut or simple operation are life-threatening events, such as they were before the discovery of penicillin.

After a successful medicinal chemistry programme targeting Gram-positive bacteria, specifically successfully completing phase I clinical trials for a novel C. diff drug, MGB-BP-3, we are now primarily concerned with developing new antibiotics that are effective against the Gram-negative pathogens from the ESKAPE pathogen set, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.

Moreover, we have already established that our MGBs synergise with both efflux pump inhibitors (EPIs) and existing antibiotics which bacteria have become resistant to. Although this synergy approach is clinically relevant, it is unlikely to afford a long term solution to AMR. Novel, single compound antimicrobial agents are ultimately required.

This seed award looks to capitalise on our synergy findings by designing single molecule conjugates between MGBs and EPIs or MGBs and antibiotics. Our goal is thus to identify novel MGBs with significant anti-Gram-negative activity that can enter clinical trials, just as we have achieved with Gram-positive active MGBs.