Scientists get up close to bacteria's toxic pumps

Nov 30, 2009
This is the outer membrane complex of the type IV secretion system. Credit: Gabriel Waksman

Scientists are building a clearer image of the machinery employed by bacteria to spread antibiotic resistance or cause diseases such as whooping cough, peptic stomach ulcers and legionnaires' disease.

The spread of antibiotic resistance amongst bacteria is a growing problem, making certain diseases increasingly difficult to treat. New strategies for attacking the bacteria are needed, yet virtually no novel-mechanism are currently in development.

Gram-negative bacteria - such as those which cause stomach ulcers and a number of other serious diseases - are particularly difficult to attack as they have a double wall, incorporating an outer membrane surrounding the bacterial cell wall, which interferes with drug penetration.

Research funded by Wellcome Trust scientists is building up a clearer picture of how Gram-negative bacteria infect the host's cells - and how they spread antibiotic resistance.

Professor Gabriel Waksman and colleagues at the Institute of Structural and Molecular Biology at Birkbeck and UCL (University College London) are studying 'type IV secretion systems', cellular 'nanodevices' which behave like pumps. These tiny machines span across the double membrane of the bacteria, pumping toxins out into host cells and antibiotic resistance genes into antibiotic-sensitive bacteria. This pump may offer a chink in the armour of Gram-negative for novel antibiotics to exploit.

Professor Waksman and colleagues have previously described the structure of the core component of the pump, using a technique known as cryo-electron microscopy. Now, in a paper published in the journal Nature, the researchers describe in detail the crystal structure of the outer membrane part of this complex. This time, the researchers used x-ray crystallography, which gives a much higher resolution than cryo-electron microscopy, allowing each atom in the structure to be identified and localised.

" gives us a much closer look at how this pump is working," explains Professor Waksman. "It's like examining a car: when you first look at a car, you see its shape, but might not understand how it works. It's only by looking under the bonnet that you can see the engine and get a clearer idea of how it works.

"The big question for us is 'how does this pump work?', and that's what we're looking at now. By taking the pump apart and seeing how its engine works, we open up the way to 'throwing a spanner in the works' and stopping the pump working."

Although the component of the pump that is described in the Nature paper is only a ten-thousandth the width of a human hair, it is the largest outer-membrane complex for which the structure is known at high resolution. It provides the first glimpse of a channel formed by more than one protein.

Toxins enter the pump through membrane channels that are integral parts of the pump. These channels are made of proteins embedded in the membrane. In large pumps, such as type IV secretion systems, these channels are very complex because they are made of many proteins: this new structure is made of three proteins, each present in fourteen copies. The extraordinary complexity of the arrangements of the proteins in the complex provides the first glimpse at the inner workings of the machinery.

"Type IV secretion systems secrete all sorts of virulence proteins and toxins," says Professor Waksman. "This structure provides a high resolution template to design effective new antibiotic treatments. In this era of ever-increasing , such a structural work provides a rich playground for antibiotics design."

Type IV secretion systems were first discovered in Agrobacterium tumefaciens, which uses the system to transfer tumour-inducing DNA into plants, causing "crown gall", which can be devastating to crops such as grape vines, sugar beet and rhubarb. However, crop scientists have been able to successfully exploit this transfer system as a way of introducing new genes into industrial crops, conferring herbicide-resistance and resistance to pathogens.

Source: Wellcome Trust (news : web)

Explore further: Researchers discover new strategy germs use to invade cells

add to favorites email to friend print save as pdf

Related Stories

Structure mediating spread of antibiotic resistance identified

Jan 08, 2009

Scientists have identified the structure of a key component of the bacteria behind such diseases as whooping cough, peptic stomach ulcers and Legionnaires' disease. The research, funded by the Wellcome Trust and the Biotechnology ...

The structure of resistance

Feb 22, 2008

A team of scientists from the University Paris Descartes has solved the structure of two proteins that allow bacteria to gain resistance to multiple types of antibiotics, according to a report in EMBO reports this month. ...

Recommended for you

Researchers discover new strategy germs use to invade cells

Aug 20, 2014

The hospital germ Pseudomonas aeruginosa wraps itself into the membrane of human cells: A team led by Dr. Thorsten Eierhoff and Junior Professor Dr. Winfried Römer from the Institute of Biology II, members of the Cluster ...

Progress in the fight against harmful fungi

Aug 20, 2014

A group of researchers at the Max F. Perutz Laboratories has created one of the three world's largest gene libraries for the Candida glabrata yeast, which is harmful to humans. Molecular analysis of the Candida ...

How steroid hormones enable plants to grow

Aug 19, 2014

Plants can adapt extremely quickly to changes in their environment. Hormones, chemical messengers that are activated in direct response to light and temperature stimuli help them achieve this. Plant steroid ...

Surviving the attack of killer microbes

Aug 19, 2014

The ability to find food and avoid predation dictates whether most organisms live to spread their genes to the next generation or die trying. But for some species of microbe, a unique virus changes the rules ...

User comments : 0