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Scientists discover MRSA's cunning tactic to evade last-resort antibiotic

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The superbug MRSA uses decoys to evade a last-resort antibiotic, reveals new research. The findings, from scientists at Imperial College London, suggest potential new ways of tackling the bacteria — most notably by disrupting the decoys.

 

Insights into the superbug

Methicillin-resistant Staphylococcus aureus is responsible for thousands of deaths around the world each year. However, because of its resistant to many different antibiotics, treatment options are limited and often ineffective.

One of the few antibiotics that can be used against MRSA is a drug of last resort called daptomycin. However, nearly a third of MRSA infections are not cured by this drug, leaving patients to cope with a poor prognosis.

The research team wanted to understand how MRSA managed to survive treatment with daptomycin and discovered that MRSA releases decoy molecules, which allow it to avoid the antibiotic.

 

How?

MRSA cells have an outer layer of fat. The antibiotic usually latches onto this fat layer and drills a hole through the outer shell thereby killing the bacteria. The decoys are made from the same type of fat as the deadly superbug's outer layer. When MRSA releases these fatty decoy molecules, the antibiotic latches onto these instead and is deactivated.

"These fat molecules act in a similar way to the decoy flares released by fighter planes to avoid a missile. The antibiotic mistakenly targets the decoys, allowing the bacteria to evade destruction. This is the first time this decoy system has been seen in MRSA," explains Dr. Andrew Edwards, lead author from the Department of Medicine at Imperial.

But the scientists also discovered when looking at these bacterial cells in the laboratory and mouse experiments that only some MRSA bacteria can use this decoy system. The team believes this is why around 30% of infections are not cured by daptomycin.

In these resistant infections, the MRSA bacteria turn off a communication system they normally use to communicate with one another. This communication system allows the bacteria to release toxins that damage human cells. However, this system also seems to interfere with decoy production.

"These MRSA bacteria 'go dark' and stop all communication. It is the switching off of this communication system that allows the decoys to work so effectively," adds Dr. Edwards, who is based at the Medical Research Council's Centre for Molecular Bacteriology and Infection at Imperial. "Our focus now is on understanding more about how these decoys are made and how they can be shut off completely to help daptomycin work better in patients."

 

Similarities with E. coli

A similar decoy mechanism has been seen in E. coli bacteria.

"Our findings suggest we may have underappreciated the importance of this decoy system, and that it probably exists in many other bacteria," says Dr. Edwards.

Further experiments revealed the release of decoys can be partially prevented using a second antibiotic, similar to penicillin, called oxacillin. Although MRSA is resistant to oxacillin, using it alongside daptomycin may allow the latter antibiotic to kill the bug more effectively.

Previous research has suggested penicillin-type antibiotics help daptomycin to kill MRSA — although scientists didn't know why. A clinical trial using the two antibiotics, led by an Australian team, is currently now underway.

Furthermore, tests revealed that a next-generation antibiotic, currently in clinical trials, seems to stop production of the fatty decoys.

"In the fight against antimicrobial resistance, we are desperately searching for new ways to treat bacterial infections like MRSA as they dangerously start to become resistant to even last-resort antibiotics. This study has uncovered a rather cunning tactic that these and possibly other bacteria use to evade current treatment, and armed with this new knowledge, we can begin to develop new and improved treatments to help tackle what is one of the biggest threats to global health," says Dr. Jonathan Pearce, head of infections and immunity at the Medical Research Council, which supported the work.

The study could not only mean a potentially new treatment option for afflicted patients. According to Professor Melanie Welham, chief executive of the Biotechnology and Biological Sciences Research Council, it also demonstrates the value of research that explores the frontiers of chemical biology in bacteria. "Finding the biological mechanisms behind why antibiotics do and don't work is crucial in the fight against anti-microbial resistance," she concludes.

This study was published in the journal Nature Microbiology, and the work was supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, or BBSRC, and the Wellcome Trust.

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