New small molecule offers hope in combating antibiotic resistance

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Researchers from the University of Oxford have developed a new small molecule that can suppress the evolution of antibiotic resistance in bacteria and make resistant bacteria more susceptible to antibiotics. The findings have been published in the journal Chemical Science.

The global rise in antibiotic-resistant bacteria is one of the top global public health and development threats, 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. Without the rapid development of new antibiotics and antimicrobials, this figure is set to rise significantly.

A new study led by researchers at the Ineos Oxford Institute for antimicrobial research (IOI) and the Department of Pharmacology at Oxford University offers hope in the discovery of a small molecule that works alongside antibiotics to suppress the evolution of drug-resistance in bacteria.

One of the ways 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 the 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.

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 ongoing work between the IOI and Oxford's Department of Pharmacology to develop new molecules to slow and/or reverse antibiotic resistance."

Jacob Bradbury, IOI DPhil student and first author of the paper

Dr Thomas Lanyon-Hogg, Principal Investigator at Oxford's Department of Pharmacology said: '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.' 

Source:
Journal reference:

Bradbury J.D, et al. (2024). Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance. Chemical Science. doi.org/10.1039/d4sc00995a.

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