Developing novel antimicrobial macrocycles against multidrug resistant bacteria that cause chronic lung infections

Pseudomonas aeruginosa (Pa) is a ubiquitous opportunistic pathogen, classified by WHO as a priority one pathogen, for which the development of new therapeutics is critical. Pa is responsible for 10-20% of nosocomial infections and possesses a suite of therapeutic resistance mechanisms. Many Pa resistance mechanisms are intrinsic; however, Pa readily acquires and utilises further mechanisms via adaptive traits, and the acquisition of new genetic material. Antimicrobial resistant Pa is a major cause of morbidity and mortality in cystic fibrosis (CF) patients (~10,000 in the UK and ~100,000 worldwide) and people with non-CF bronchiectasis (50,000-300,000 in the UK alone). Once they have colonised the CF lung, Pa isolates can establish a multidrug resistant infection, rapidly reducing treatment options. These multidrug resistant infections become impossible to eradicate, leading to dramatic loss of lung function.
Previously, a divergent commercial macrocycle compound library was screened against clinical strains of multidrug resistant Pa. Novel hits were generated; these were either resistance-breakers which potentiated existing antibiotics, or direct-acting antimicrobials which inhibited resistant Pa. A cheminformatics approach was used to cluster and prioritise the compounds, and chemical synthetic routes for resynthesis and derivation of the prioritised compounds were then established.
The research will encompass investigations of the mechanisms of the prioritised hits against resistant Pa using a combination of microbiological, genomic, and chemical proteomics approaches. The prioritised hits will be profiled against known resistant Pa strains to evidence any cross-resistance with known antibiotics or potentiators. Whole genome sequencing will be used to establish and identify mutations conferring resistance in known resistant isolates relative to baseline strains. For the chemical proteomics approach, photoreactive chemical probes mimicking structures and biological activities of the selected hits will be used to tag and enrich protein targets of interest. They will also be used to investigate the interactions between the chemical probes and potential targets at the molecular level.
This interdisciplinary project intends to address a public health issue at the interfaces between medicinal chemistry, chemical biology, microbiology, and chem/bioinformatics. The overall aim is to further both antimicrobial resistance research and antibiotic discovery.