A new way of designing antibiotics could support the discovery of new treatments for drug-resistant infections.
It could also help revive antibiotics that have lost effectiveness because bacteria have evolved over time to survive the drugs meant to kill them.
The study, led by researchers at King’s College London and published in the Journal of Medicinal Chemistry, describes a new approach called ‘Efflux Resistance Breaker’, or ERB, which is designed to overcome one of the ways bacteria escape antibiotic treatment.
Many bacteria use molecular pumps, known as efflux pumps, to push antibiotics out of the cell before the drugs can reach levels high enough to kill them. This reduces the amount of antibiotic inside the bacteria and allows resistant infections to survive.
Chemically redesigned
The King’s-led team has shown that antibiotics can be chemically redesigned so they are less easily removed by these pumps. This allows the antibiotic to remain inside the bacterial cell at higher concentrations, restoring its ability to kill bacteria even when resistance mechanisms are present.
Importantly, the work shows that the ERB approach could support a new way of developing antibiotics by building resistance-breaking properties directly into their design.
Unlike previous strategies that have tried to combine antibiotics with separate efflux pump inhibitors, this new approach builds resistance-breaking properties directly into the antibiotic molecule. This means the antibiotic is designed to protect itself from being pumped out.
Reviving antibiotics
Professor Khondaker Miraz Rahman, a Professor of Medicinal Chemistry from King’s College London, who led the study said: “Antimicrobial resistance is rising, but the number of truly new antibiotics in development remains worryingly low. Our work shows that we can redesign antibiotics so they stay inside bacterial cells at higher concentrations and overcome resistance mechanisms that would normally make them ineffective. This approach could help us design better new antibiotics, but it could also help revive existing antibiotic classes that bacteria have learned to defeat.”
Professor J. Mark Sutton, from the UK Health Security Agency, who is a key collaborator on this project, said: “Efflux pumps are a major cause of antibiotic resistance because they reduce the concentration of drug inside the bacterial cell. This study shows that rational chemical design can be used to overcome that problem. By building efflux resistance directly into the antibiotic, we may be able to restore activity against bacteria that are no longer controlled by current drugs.”
Proof of concept
The study provides an important proof of concept for antibiotic discovery. It shows that maintaining high intracellular antibiotic concentration can help overcome resistance, including in bacteria that already show reduced susceptibility to existing antibiotics.
The researchers believe the ERB platform could be used as a general strategy to design antibiotics with built-in resilience to efflux-mediated resistance. The manuscript describes ERB technology as a framework for developing next-generation antibiotics and for revitalising existing drugs.
The team will now focus on commercialising the ERB technology and advancing antibiotics developed using this strategy towards clinical development, with the aim of translating this discovery into new treatment options for drug-resistant infections.
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