Breaking the Phalanx: Overcoming Bacterial Drug Resistance with Quorum Sensing Inhibitors that Enhance Therapeutic Activity of Antibiotics.

Antibiotic-resistant bacterial infections loom over humanity as an increasing deadly threat. There exists a dire need for new treatments, especially those that synergize with our existing arsenal of antibiotic drugs to help overcome the gap in antibiotic efficacy and attenuate the development of new antibiotic-resistance in the most dangerous pathogens. Quorum sensing systems in bacteria drive the formation of biofilms, increase surface motility, and enhance other virulence factors, making these systems attractive targets for the discovery of novel antibacterials. Quorum sensing inhibitors (QSIs) are hypothesized to synergize with existing antibiotics, making bacteria more sensitive to the effects of these drugs. In this study, we aimed to find the synergistic combinations between the QSIs and known antibiotics to combat the two deadliest hospital infections - and . We mined biochemical activity databases and literature to identify known, high efficacy QSIs against these bacteria. We used these data to develop and validate a Quantitative Structure-Activity Relationship (QSAR) model for predicting QSI activity and then employed this model to identify new potential QSIs from the Inxight database of approved and investigational drugs. We then tested binary mixtures of the identified QSIs with 11 existing antibiotics using a combinatorial matrix screening approach with ten (five of each) clinical isolates of and . Amongst explored drug combinations, 31 exhibited a synergistic effect, including mixtures involving naldemedine and telotristat, two drugs predicted by our model with previously undescribed QSI activity. Although no mixture inhibiting all the strains was found, piperacillin combined with curcumin, ketoprofen, indomethacin, and piroxicam demonstrated the broadest antimicrobial action. We anticipate that further preclinical investigation of these combinations of novel repurposed QSIs with a known antibiotic may lead to novel clinical candidates.