Superbug defences shattered by breakthrough drug design (Wired UK)



A team of molecular scientists has uncovered a way to disable
the defensive structure of the multidrug-resistant gram-negative
bacteria, paving the way for new antibiotics that target this

Gram-negative bacteria are often found in the gut, but can
become resistant to antibiotics and can cause infections of the
blood, surgical sites, as well as pneumonia and meningitis. Misuse
of antibiotics has led to a worrying trend of drug-resistant
bacteria in circulation, leading to the emergence of “superbugs”,
and it has been singled out as one of the greatest single problems threatening the future of our health.

“These drug resistance numbers increase every year, making
antibiotics useless, which results in hundreds and thousands of
patient’s deaths,” Changjiang Dong, from the University of East
Anglia Norwich Medical School, told “So we are trying
to find a way to solve this drug resistance problem.”

He and his team have now found a way around this particular
bacterium’s defences, according to a paper published in
Nature: lipopolysaccharide (LPS). This is a molecule made
up of a tough outer membrane that the UAE team wanted to crack.
Until now, how the molecule’s transport proteins are utilised to
create that membrane has been unknown. 

“This bacterium can build up the outer membrane, which is
important for their multidrug resistance survival. So we tried to
find out how the bacteria uses the machinery we call Lpt D and E
[two transport proteins] to build up the outer membrane.”

“Our exciting research showed how the bacteria used the proteins
to build up the outer membrane, and also the path and the gate of
this machinery. Then we showed if we block the path or the gate of
this machinery, the multidrug-resistant bacteria would die. This
allowed us to create special drugs to target it.”

The team has developed a detailed model of how the transport
proteins function and move the building blocks of the molecular
barrier to the surface. Now that they have the structure, they can
design targeted drugs and test its function. Dong predicts the
first drugs could be with us in a few years.

“We hope we can develop a new class of antibiotics to help
people to control multidrug resistance. The number of superbugs are
increasing at an unexpected rate. This research provides the
platform for urgently-needed new generation drugs.”

Lead author on the paper, PhD student Haohao Dong, added: “The
really exciting thing about this research is that new drugs will
specifically target the protective barrier around the bacteria,
rather than the bacteria itself. Because new drugs will not need to
enter the bacteria itself, we hope that the bacteria will not be
able to develop drug resistance in future.”



Investment in new antibiotics has floundered in recent decades,
but Changjiang Dong is hopeful that now that funding is
starting to support this type of research (for the UAE team, the
Wellcome Trust), big pharma is starting to show interest. 

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18 June 2014 | 5:24 pm – Source:

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