What is the problem?

In the continuing absence of new antibiotics, particularly agents active against Gram-negative bacteria, new approaches are necessary to prolong the therapeutically useful lifetime of existing drugs. One such approach is to co-administer antibiotics with inhibitors of specific resistance enzymes in order to restore the effectiveness of key antibiotic classes against resistant strains. However, suitable inhibitors are available for only a small subset of resistance enzymes.

A potential solution

An interdisciplinary team led by Prof Jim Spencer (School of Cellular and Molecular Medicine) are seeking to exploit their growing mechanistic understanding of resistance enzymes to identify and develop new routes to their inhibition and assesss candidate inhibitors for their effectiveness against circulating resistant organisms and strains. The team have employed in silico methods to identify candidate inhibitors, structural and biochemical methods to evaluate inhibitor effectiveness in vitro and microbiological susceptibility assays to assess the effect of combinations of antibiotic and resistance inhibitor against resistant bacterial strains. 

Outcome and next steps

The team have evaluated a number of inhibitor classes active against a range of beta-lactamases to describe their interactions with target enzymes and their effectiveness as part of antibiotic combinations against resistant bacteria. In silico assays of beta-lactamase:inhibitor reactions identify how ease of breakdown of inhibitor complexes reflects inhibitor effectiveness against different target enzymes. New inhibitor classes investigated include phosphonates, cyclobutanones, thiazolidines and bisthiazolidines against metallo-beta-lactamases; diazabicylooctanones and monocyclic boronates against serine beta-lactamases; and bicyclic boronates against both beta-lactamase classes. The work has identified new inhibitor classes and new modes of inhibitor action and established the activity spectrum of specific inhibitor combinations against challenging resistant organisms. Earlier stage investigations of the transferable colistin resistance determinant MCR-1 have focused on developing assays and tool compounds with which to validate in vitro the results of in silico inhibitor identification experiments. Next steps include assessing the suitability of some of these new inhibitor classes for preclinical development by evaluating their effectiveness in a wider range of resistant clinical strains and investigating their specificity and potential toxicity towards eukaryotic targets.