Harnessing 'brute force' could be key to creating ne...

"Antibiotics 'seen using brute force to kill bugs'',"BBC News reports. The hope is that researchers could replicate the effect to create new antibiotics that could help combat the continuing threat of antibiotic resistance.

The BBC reports on an early stage laboratory study investigating how our strongest antibacterial drugs target and destroy "hard to kill" bacteria such as the "superbug" methicillin-resistant Staphylococcus aureus (MRSA).

The answer lies in how well the drug can bind (stick) to target protein molecules on the bacterial surface membrane. When there is sufficient binding across the membrane, this exerts a level of mechanical force that causes the membrane to literally break apart and the cell is destroyed. One way of picturing this process is somebody ripping apart a bag of frozen peas spreading the contents everywhere.

The researchers hope that further study will be able to build on these findings and develop new or modified antibiotics that have better ability to interact with targets on the surface membrane and so destroy the bacteria.

With increasing numbers of bacteria developing resistance to drugs, it is a major public health concern whereby we could reach a point where some infections become untreatable.

So further developments from this study are eagerly awaited.

Where did the story come from?

The study was carried out by researchers from University College London, the Royal Free Hospital, the University of Cambridge, and other institutions in Kenya, Australia and Switzerland. The study received funding from various sources including the EPSRC Interdisciplinary Research Centre in Nanotechnology and EPSRC Grand Challenge in Nanotechnology for Healthcare.

The study was published in the peer-reviewed scientific journal Nature: Scientific Reports and the article is free to read online.

The UK’s media reporting of the study was accurate.

What kind of research was this?

This was a laboratory study looking at the mechanisms by which antibiotics target and destroy multi-resistant bacteria – bacteria resistant to more than antibiotics.

As the researchers say, the increase in the number of bacteria that are developing resistance to antibiotics is a major health concern. To tackle this there is a need to develop new antibiotics or new mechanisms to combat infection.

This study centred on some of the strongest antibiotics that are normally reserved to treat severe bacterial infections that are resistant to other antibiotics, such as methicillin-resistant staphylococcus aureus (MRSA) – methicillin was an early penicillin antibiotic).

It looked at the way they bind to specific protein targets on the bacteria and the force exerted to kill the bacteria.

What did the researchers do?

The research involved studying how four strong antibiotics bind to protein targets on both susceptible bacteria and multi-resistant bacteria.

The four antibiotics were vancomycin, oritavancin, ristomycin and chloroeremomycin. Vancomycin is often the "last resort" antibiotic used to treat severe MRSA infections and clostridium difficile bowel infections.

Oritavancin is a new antibiotic used to treat complicated skin and soft tissue infections. The latter two are not currently licensed antibiotics.

Researchers measured signals that indicated the level of mechanical stress or force exerted at the cell surface when antibiotics bound to the membrane targets. They looked at the effects of different antibiotics and concentrations of antibiotic.

What did they find?

When the antibiotics bind to the protein targets on the bacterial membrane they produce a mechanical strain that increases with the number of bound targets – that is, as the antibiotic dose or concentration increases.

At a particular strain they weaken the overall strength of the cell membrane, making it unable to resist the osmotic pressure coming from inside the cell. This causes the bacteria to eventually break apart and die.

The researchers found the way in which the four different antibiotics bind to membrane targets of susceptible (non-resistant) bacteria was the same. However, there was significant difference in the mechanical force they exerted on the resistant bacterial targets.

Notably they found the binding force of oritavancin was 11,000 times stronger than that of vancomycin.

What did the researchers conclude?

The researchers conclude: "Using an exactly solvable model, which takes into account the solvent and membrane effects, we demonstrate that drug-target interactions are strengthened by pronounced polyvalent interactions catalysed by the surface itself".

They suggest the findings "further enhance our understanding of antibiotic mode of action and will enable development of more effective therapies".

Conclusions

This laboratory study furthers understanding of the mechanisms by which antibacterial drugs target and destroy bacteria.

The answer seems to lie in how effectively the drug can bind to target molecules on the bacterial surface membrane. When the force of this binding exerts sufficient mechanical strain on the cell surface, then the bacteria breaks apart and is destroyed.

It shows that the strongest antibacterials that we have, such as vancomycin, are currently not infallible.

That we could reach a point where we have bacterial infections that not even the strongest antibiotics are able to fight is a major public health concern. It is hoped that further research will be able to build on these findings and develop new or modified antibacterials that have better ability to interact with the bacterial surface membrane and so destroy the cells.

Lead researcher Dr Jospeh Ndieyira is quoted in BBC News as saying: "No-one has really thought about antibiotics using mechanical forces to kill their targets before. This will help us create a new generation of antibiotics to tackle multi-drug resistant bacterial infections, now recognised as one of the greatest global threats in modern healthcare."

You can help combat the threat of antibiotic resistance yourself by:

recognising that most coughs, colds and stomach bugs are viral and do not need antibiotics
if prescribed antibiotics, always take them exactly as prescribed and take the full course, even if you start to feel better
never share them with anyone