Tuesday, March 22, 2016

Breakthrough in fight against antibiotic-resistance: Discovery of bacteria’s 'Achilles heel' could lead to new drugs

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Scientists across the globe have been searching for a way to tackle antibiotic-resistant bacteria.

But now, experts from University of Copenhagen have discovered a previously unknown weakness in the bugs.

The so-called Achilles heel is a crucial step in.....
bacteria’s energy metabolism – a proton pump that leaks when the bacteria becomes ‘dangerously sour’ due to a pH imbalance.

This discovery could lead to the development of drugs that exploit this inherent weakness, scientists hope.

Study author Dr Nikos Hatzakis said: ‘I believe the leaking mechanism acts as a safety valve in the bacteria.

‘If we can design a drug which targets such safety valve in proton pumps, it would be a very powerful antibiotic indeed, so the leak state is a serious weakness, an Achilles heel.’

Bacteria must pump protons in and out of their cells to maintain a finely tuned imbalance between the pH value – inside and out.

That imbalance is the power source in the microbe’s production of ATP, or adenosine triphosphate - which powers most biological processes in the bacteria.

It is similar to how a difference in water pressure is the power source for a hydroelectric generator, the scientists explained.

Thus, the team set out to determine if manipulating the pH imbalance would be a powerful way to disable germs.

The scientists conducted a series of experiments, ultimately finding a way to potentially manipulate the generated pH balance through manipulating the proton pumps.

They determined that when the bacteria becomes sour inside, the pumps may leak.

Dr Katzakis said that in other words, it leaks when the imbalance between inside and out becomes too large.

The proton pump is tiny – an enzyme only five nanometers across – and is located on the surface membrane of the bacteria.

To measure its leakage, the scientists ‘surgically’ removed the pump from the membrane.

They then placed it on a microscope slide – but could not determine enough from looking alone.

Researcher Sune Jorgensen said: ‘We wanted to be able to control the pump: To turn it on and off.

‘In order to do that, we constructed a miniscule electrode [and] coated the microscope slide with 30 nanometers of gold.

‘This is thin enough to see through, but electrically conductive, so it allowed us to switch the pump on and off with an electrical current.’

The discovery of the bacterial safety valve goes against the classical biological concept that enzyme and proteins are either activated or de-activated.

Dr Hatzakis noted that to find that one is running, but not working optimally, is surprising.

He said: ‘The result is obviously interesting because of its possible application in antibiotics research, but it also answers a fundamental question about how enzymes work.

‘Deciphering this behavior required a unique combination of chemistry insights, biology and nano-technology.

‘No one had ever looked at just one pump at work, before, but we managed to look at one or very few at a time. And that’s pretty cool.’

The study was published in the Journal of the American Chemical Society.

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