Powerful new tool gives hope of overcoming antibiotic resistance.

Antibiotics

New antibiotic target may help mankind win the on-going battle against antibiotic resistance.
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Bacterial resistance to antibiotics has become one of the biggest health concerns of the 21st century. New work into disabling rather than destroying bacteria may help mankind win the on-going battle against bacterial disease and antibiotic resistance.

A nano-machine embedded in a bacterial membrane dubbed TAM was discovered by a team working in Monash University, Melbourne Australia. TAM (Translocation and Assembly Module) acts as a biological pump that transports disease-causing protein molecules from where they are produced inside cells to the outer surface. These molecules then allow the bacteria to stick to surfaces in hosts, preparing the bacteria for infection. "We found that the TAM exists in many disease-causing bacteria, from micro-organisms that cause whooping cough and meningitis, to hospital-acquired bacteria developing resistance to current antibiotics," says Dr Joel Selkrig, of Monash University, Australia, who discovered the role of the TAM nanomachine in 2012.

The scientists experimented by knocking out TAM in bacteria, and noticed that in these mutants lacking TAM there were major proteins missing from the outer membrane. “Bacterial mutants lacking TAM were inferior at causing disease, inferring a role for the TAM machinery in bacterial pathogenesis,” says Professor Trevor Lithgow, Leader of the team investigating TAM.

Eliminating TAM means that these harmful proteins can’t make their way out of the bacteria, so can’t perform their disease related functions. This opens up the possibility of designing a whole new class of drugs.

Protein targeting and assembly pathways are fundamental aspects of cell biology, but measuring the internal movement of the component parts within these biological nanomachines has been a major technological challenge. Professor Lithgow and his team brought the problem to ISIS where they hoped the technique of magnetic contrast neutron reflectometry (MCNR) might offer the means for studying the TAM mechanism in detail. They successfully reconstituted a membrane containing the TAM onto a gold surface and using MCNR to work out its structure with two proteins TAMB and TAMA located in the inner and outer membrane layers.

Having reconstituted the nanomachine, they were then able to understand how it behaved when it presented with a sample protein known as AG43. The team discovered that while the outer protein TAMA initiated the movement of the protein to the membrane its partner TAMB was responsible for regulating this process.  This demonstrated that MCNR is a powerful new means of understanding molecular movements in membrane proteins and in diverse cellular processes - and there are potentially huge benefits within the foreseeable future.

In understanding the how the TAM complex functions they have discovered a potential target for antibacterial drugs. “We are also quite excited about the prospect of TAMA as a druggable target in bacteria,” says Lithgow, “If you can block virulence factor transport in pathogenic bacteria, you will reduce bacterial virulence. So if you could knock out the TAM function using something like a small molecule or antibody, and thereby knock out secretion of a whole range of virulence factors, you could reduce bacterial pathogenicity and disease.”

 The beauty of drugs designed to inhibit the TAM nanomachine mechanism is that the drugs would probably not kill the bacteria. They would simply “deprive them of their molecular weaponry — thereby disabling the disease process.” explains Selkrig. So these drugs would not affect the bacteria’s ability to grow and survive as a population, causing minimal selective pressure to develop resistance mechanisms. "Inhibiting the TAM complex and allowing the bacteria to stay alive in the body without causing disease may reduce the likelihood of them evolving a counter to the antibiotic drugs. It's a way to give the body's immune system a head start by blunting the sword or disarming the bacteria, taking away their weaponry."

Amy Redhead

Research date: October 2014

Further Information

Shen, H., Leyton, D., Shiota, T., Belousoff, M., Noinaj, N., Lu, J., Holt, S., Tan, K., Selkrig, J., Webb, C., Buchanan, S., Martin, L. and Lithgow, T. (2014). Reconstitution of a nanomachine driving the assembly of proteins into bacterial outer membranes. Nat Comms, 5, p.5078.

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