University of Oxford researchers have developed a new small molecule that can suppress the evolution of antibiotic resistance in bacteria.
Antibiotic resistance is a top global public health threat with many common infections becoming increasingly difficult to treat. It is estimated that drug-resistant bacteria are already directly responsible for around 1.27 million global deaths each year and contribute to a further 4.95 million deaths. Rapid development of new antibiotics and antimicrobials is necessary to combat antibiotic 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 ongoing work between the IOI and Oxford’s Department of Pharmacology to develop new molecules to slow and/or reverse antibiotic resistance,” commented Jacob Bradbury, IOI DPhil student and first author of the paper.
The findings are available in the journal Chemical Science.
New hope for antibiotic resistance
Researchers at the Ineos Oxford Institute for Antimicrobial Research (IOI) and the Department of Pharmacology at Oxford University discovered a small molecule that works alongside antibiotics to suppress the evolution of drug resistance in bacteria.
One way that bacteria become resistant to antibiotics is due to new mutations in their genetic code. Some antibiotics (such as fluoroquinolones) work by damaging bacterial DNA, causing the cells to die. However, 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 can accelerate the development of resistance to antibiotics. In the new study, the Oxford scientists identified a molecule capable of suppressing the SOS response, ultimately increasing the effectiveness of antibiotics against these bacteria.
First study to demonstrate the suppression of antibiotic resistance evolution
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 lives harmlessly on the skin, but if it gets inside the body, causes a serious infection which requires 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 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.
The team 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 that demonstrates that an inhibitor of the SOS response can suppress the evolution of antibiotic resistance in bacteria. Furthermore, 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.
