Researchers from the Ineos Oxford Institute for antimicrobial research (IOI) and the Department of Pharmacology at Oxford University, have developed a new small molecule that can suppress the evolution of antibiotic resistance in bacteria and make resistant bacteria more susceptible to antibiotics.
One of the ways that bacteria become resistant to antibiotics is due to mutations in their genetic code. Some antibiotics such as fluoroquinolones work by damaging bacterial DNA. This DNA damage can trigger a process known as the ‘SOS response’ in the affected bacteria. The SOS response repairs the damaged DNA in bacteria and increases the rate of genetic mutations, which in turn speeds up the development of resistance to the antibiotics. Scientists at the University of Oxford have found a molecule capable of suppressing the SOS response, ultimately increasing the effectiveness of antibiotics against these bacteria.
This new study published in Chemical Science reports the development of a new small molecule that works alongside antibiotics to suppress the SOS response in bacteria. The researchers studied a series of molecules previously reported to increase the sensitivity of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics, and to prevent the MRSA SOS response. MRSA is a type of bacteria that usually lives harmlessly on the skin. But if it gets inside the body, it can cause a serious infection that needs immediate treatment with antibiotics. MRSA is resistant to all beta-lactam antibiotics such as penicillins and cephalosporins.
Researchers modified the structure of different parts of the molecule and tested their action against MRSA when given with ciprofloxacin, a fluoroquinolone antibiotic. This identified the most potent SOS inhibitor molecule reported to-date, called OXF-077. When combined with a range of antibiotics from different classes, OXF-077 made these more effective in preventing the visible growth of MRSA bacteria.
In a key result, the team then tested the susceptibility of bacteria treated with ciprofloxacin over a series of days to determine how quickly resistance to the antibiotic was developing, either with or without OXF-077. They found that the emergence of resistance to ciprofloxacin was significantly suppressed in bacteria treated with OXF-077, compared to those not treated with OXF-077. This is the first study to demonstrate that an inhibitor of the SOS response can suppress the evolution of antibiotic resistance in bacteria. Moreover, when resistant bacteria previously exposed to ciprofloxacin were treated with OXF-077, it restored their sensitivity to the antibiotic to the same level as bacteria that had not developed resistance.
These findings suggest OXF-077 is a useful tool molecule to further study the effects of SOS response inhibition in bacteria, and for the treatment of antibiotic-resistant infections. Further work is needed to test the suitability of these molecules for use outside of lab settings, and will form part of on-going work between at the IOI and the Department of Pharmacology to develop new molecules to slow and/or reverse antibiotic resistance.
This is a great example of what can be achieved through interdisciplinary collaboration between microbiologists in the IOI and chemical biologists in Pharmacology. The AMR crisis presents technical obstacles in numerous areas, and if the challenges we face as scientists are not confined to a single scientific discipline, then the solutions will not be either.
