Project Details
Description
Before the introduction of the first antibiotic in 1930, infectious diseases were the predominant cause of death globally and the average life expectancy was 47. The introduction of antibiotics revolutionized medicine, and by 1970, life expectancy increased by 20 years. Presently, antibiotic resistance is threatening these medical achievements; what we currently consider ‘ordinary’ infections could once again become fatal.
One of the main resistance strategies of Gram-negative bacteria is to pump out antibiotics from their cells via efflux pumps. Being constitutively present, efflux pumps represent the bacterium´s first survival kit against antibiotics. Of particular importance are efflux pumps of the RND family, which span the periplasm and connect inner and outer membranes creating the bacterium’s ‘emergency exit’. To counteract this intrinsic resistance strategy, higher antibiotic doses are used. Such large doses pressurize bacteria to overproduce efflux pumps. To halt this dangerous cycle, efflux pumps must be disarmed.
Efflux pump inhibitors (EPIs) are compounds that disarm efflux pumps, thereby impeding the clearance of the antibiotic from the cell and restoring its efficiency. By blocking efflux pumps, we can reduce antibiotic dosage, as well as the selective pressure on bacteria, potential side effects for patients, and treatment costs. Unfortunately, due to high toxicity, no available synthetic EPIs are in use.
Over time, plants have developed effective weaponry to defend themselves against infections. Plants have been able to deliver effectively their antimicrobials inside bacteria by disarming the action of efflux pumps. In this VENI, I will harness the plant’s defense metabolism to propose natural ‘phytoEPIs’ against Gram-negative efflux pumps. I will combine whole-cell-based assays, crystallography and computer modelling tools to unravel molecular signatures for effective efflux pump inhibition and fundamental understanding on the mechanism of phytoEPIs. Ultimately, candidate phytoEPIs can be used to help decrease the global burden of antibiotic resistance.
One of the main resistance strategies of Gram-negative bacteria is to pump out antibiotics from their cells via efflux pumps. Being constitutively present, efflux pumps represent the bacterium´s first survival kit against antibiotics. Of particular importance are efflux pumps of the RND family, which span the periplasm and connect inner and outer membranes creating the bacterium’s ‘emergency exit’. To counteract this intrinsic resistance strategy, higher antibiotic doses are used. Such large doses pressurize bacteria to overproduce efflux pumps. To halt this dangerous cycle, efflux pumps must be disarmed.
Efflux pump inhibitors (EPIs) are compounds that disarm efflux pumps, thereby impeding the clearance of the antibiotic from the cell and restoring its efficiency. By blocking efflux pumps, we can reduce antibiotic dosage, as well as the selective pressure on bacteria, potential side effects for patients, and treatment costs. Unfortunately, due to high toxicity, no available synthetic EPIs are in use.
Over time, plants have developed effective weaponry to defend themselves against infections. Plants have been able to deliver effectively their antimicrobials inside bacteria by disarming the action of efflux pumps. In this VENI, I will harness the plant’s defense metabolism to propose natural ‘phytoEPIs’ against Gram-negative efflux pumps. I will combine whole-cell-based assays, crystallography and computer modelling tools to unravel molecular signatures for effective efflux pump inhibition and fundamental understanding on the mechanism of phytoEPIs. Ultimately, candidate phytoEPIs can be used to help decrease the global burden of antibiotic resistance.
| Status | Active |
|---|---|
| Effective start/end date | 1/01/20 → … |
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.