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Study describes pump mechanism that enables bacteria to evade antibiotic attack

26 April 2013

Researchers have uncovered details of a mechanism that bacteria use to avoid the effects of antibiotics, which could pave the way for developing new drugs to counteract antibiotic resistance.

The discovery, from researchers at Durham University and the University of Birmingham, gives the first clear insight into how molecular pumps in the cell wall of some types of bacteria work to actively pump antibiotics out of the cell, enabling the bacteria to avoid their toxic effects.

Certain types of bacteria are a scourge of the hospital environment because they are extremely resistant to antibiotics and consequently difficult, if not impossible, to treat. This group of bacteria is classified as 'Gram-negative' because their cells have a double membrane or outer layer, in contrast to Gram-positive bacteria, which just have one outer layer.

It is difficult for antibiotics to penetrate these bacterial cells, not only because of the double membrane but also because the cells have molecular 'pumps' that quickly reject anything that interferes with protein building within the cell and the development of the protective cell wall. The pumps are made up of three different proteins, which work together to bring about the movement that is required to transport the antibiotic out of the bacterial cell.

Professor Adrian Walmsley from Durham University's School of Biological and Biomedical Sciences explains: "By investigating how these pumps function, we have been able to identify the molecular events that are involved in binding and transporting an antibiotic from the cell. This advance in our understanding will ultimately aid the development of 'pump blockers'. This is important because these pumps often confer resistance to multiple, structurally unrelated, drugs, which means that they could also be resistant to new drugs which have never been used before."

Dr Vassiliy Bavro from the Institute of Microbiology and Infection at the University of Birmingham added: "This study greatly expands our understanding of the mechanistic aspects of the pump function, and in particular challenges our previous concepts of energy requirements for pump assembly and cycling. By elucidating the intricate details of how these essential nanomachines come together, it also provides a new working model of their functional cycle in general, paving the way to development of novel approaches to disrupting their function."

Antibiotic resistance is a global problem. The World Health Organization (WHO) estimates that for tuberculosis alone, multidrug resistance accounts for more than 150 000 deaths each year. The UK's Chief Medical Officer recently described the threat of antibiotic resistance as "catastrophic" and referred to a "ticking time bomb" that will turn common infections into incurable killers and make routine surgeries a high-risk gamble.

Dr Ted Bianco, Acting Director of the Wellcome Trust, said: "A world without antibiotics is a world where simple surgery becomes a life-threatening procedure, where a scratch from a rose might prove fatal, and where diseases like tuberculosis return with a ferocity not seen in Britain since the Victorian era. This is why fundamental research to understand the mechanisms of antibiotic resistance is so important. Only when we know what we're up against can researchers begin to design new antibacterial agents to help us win the war against bacterial infections."

Image caption: Neisseria gonorrhoeae. Credit: Wellcome Library, London.

Reference

Janganan TK et al. Tripartite efflux pumps: energy is required for disassociation, but not assembly or opening of the outer membrane channel of the pump. Mol Microbiology 2013:83(3);590-602.

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