Researchers at King's College London have developed a new approach to antibiotic design that could help combat drug-resistant infections and even restore the effectiveness of existing antibiotics that have lost their potency. The study was published in the Journal of Medicinal Chemistry.

One of the biggest challenges in modern antimicrobial resistance is that bacteria have evolved ways to defend themselves against antibiotics.

A major defense mechanism involves so-called efflux pumps—molecular systems that actively expel antibiotics from bacterial cells before the drugs have a chance to work.

As a result, the concentration of the antibiotic inside the bacterium remains too low to kill the infection.

To address this problem, the researchers developed a new strategy called Efflux Resistance Breaker (ERB). The concept involves chemically modifying antibiotic molecules so that bacteria find it more difficult to pump them out.

In other words, the antibiotic not only attacks the bacterium but is also designed to be less susceptible to the bacterium’s own defense mechanisms.

This sets ERB apart from previous approaches, which relied on combining antibiotics with separate compounds that inhibit efflux pumps. In the new strategy, resistance-breaking properties are built directly into the antibiotic molecule itself.

According to Professor Khondaker Miraz Rahman, the approach could open two important avenues:

  • the development of new antibiotics with enhanced resistance to bacterial defense mechanisms;

  • the revival of existing antibiotic classes whose effectiveness has been diminished by antimicrobial resistance.

Co-author Professor J. Mark Sutton of the UK Health Security Agency noted that efflux pumps are one of the primary drivers of bacterial resistance because they dramatically reduce drug concentrations inside bacterial cells.

If antibiotics can be retained within the bacteria, even resistant strains may once again become susceptible to treatment.

The researchers emphasize that the work currently represents a proof of concept. However, the findings point to a promising pathway for developing a new generation of antibiotics capable of overcoming bacterial resistance.

The team plans to further develop the ERB technology and advance it toward clinical applications, including potential commercialization and the creation of new antibacterial medicines.