Mechanism of Action and Lead Optimisation of a Novel Antimicrobial Class

Antimicrobial resistance, AMR, is globally responsible for 1.2 million annual fatalities. Failure to address the issue by 2050 could result in 10 million deaths per year, costing the global economy £66 trillion. To put this in to context, the predicted death rate for cancer is 8.2 million by the same year. As current antibiotics fail minor injuries, like a scratch on the knee, could soon become fatal. To address this emergency, the World Health Organisation, WHO, has called for novel methods to treat antibiotic resistant infections. Our team are directly answering this call, in line with the UK Government's 20-year vision to control and contain AMR by 2040\. As part of a highly skilled team, MetalloBio have developed two novel antimicrobial compounds to treat these extensively-drug resistant infections where other antibiotics are failing.

The compounds exhibit comparable activities to clinical antibiotics but, crucially retain this high activity against drug-resistant bacteria, including bacterial strains the WHO has declared as critical priorities for new treatments. The complexes themselves have a modular synthesis. Like Lego, we can exchange the "building blocks" of our current leads to make a whole series of potential drugs. Both compounds have been found to be non-toxic to human cell lines in wax moth larvae and rodents. In addition, both compounds cleared a fatal infection from the larvae using a single dose.

This project will directly build upon our preclinical data, including already determined toxicology and pharmacokinetic profiles in mice, accelerating the technology's development, reducing our time to market. This will increase the probability of the compounds successfully reaching the clinic. The full mechanism of action of both compounds will be studied and the efficacy of both compounds against a P. aeruginosa efficacy model determined. These experiments will de-risk the technology, allowing its progression onto medium animal models.

Our compounds explore a new area of antimicrobial chemistry, their structures are radically different to any antibiotics in the clinic. This will reduce the likelihood of resistance emerging, increasing the capability to treat infections and improve patient quality of life.