Sunday, 18 January 2015

Teixobactin - grown in soil with the potetnial to save lives

Antibiotic resistance is one of our biggest medical challenges. The dangers resistance brings were compared to those of terrorism and climate change by the Chief Medical Office for England, Prof. Dame Sally Davies, in 2013, and more recently the World Health Organisation have called it a "major global threat.” These fears arise from the abundance of bacteria that can infect us. Imagine getting a small cut and an infection. For the past 70 or so years that hasn’t been an issue; you’d simply head to your GP and receive a short course of antibiotics to clear the infection. If antibiotic resistance continues its trend of becoming increasingly widespread then this treatment may not be an option, a small cut could be lethal. In bigger contexts, any form of surgery would carry huge risks, childbirth would become dangerous for the mother (and child), and I could go on. With increasingly widespread resistance to our current crop of antibiotics, it’s clear that we need new chemicals. Yet no new treatments have made it to clinics since 1987. However, with a new study published online by the journal Nature on the 7th January 2015, that could be on course to change.
Alexander Flemming - discoverer of the first antibiotic penicillin.

The first question to discuss is why the drought in new antibiotics? The first antibiotic was discovered in 1928 by Alexander Flemming (penicillin) and the so called 'Golden age' of discovery ensued between 1940 and 1960, where the vast majority of current antibiotic classes were discovered. Unlike most other drugs, antibiotics are natural products produced by bacteria or fungi (to kill competition for the most part). Discovery of new antibiotics is therefore dependent on finding organisms that produce them. This is where the problem lies, most of the resources have been tapped out. Over the past 70 or so years since mass production of antibiotics began, countless bacteria and fungi have been tested for production of antibiotic products - a brick wall was eventually hit. It’s not to say that every organism has been tested, but all that can easily be grown in a laboratory have. In order to develop new antibiotics, new organisms need to be grown and tested for products that we could use. This was the approach taken by the study I’ll get to shortly.
Penicillin killing bacteria on an agar plate.
Before talking about that work, however, I’d like to briefly talk about resistance. As mentioned, antibiotics are natural products produced by bacteria and fungi, which makes them inherently flawed. Antibiotics function by either slowing growth, or killing bacteria; therefore any bacterium that produces an antibiotic needs to be insensitive to it. It would be useless to produce a chemical that can kill bacteria, if you yourself are killed by it. Through evolution, there are mechanisms in place so that the producer organisms can counteract any actions of their antibiotic. These can take many forms, for instance enzymes that alter the chemical properties of the antibiotic, or physical pumps that can remove it from the bacterial cell. While it’s not an issue for one bacteria to have these mechanisms in place, there is a phenomenon known as horizontal gene transfer that can occur in bacteria. When animals give birth, or bacteria divide, this can be considered vertical gene transfer, since genes are transferred to a new generation. However, in horizontal gene transfer, it is possible for one bacterium to transfer genetic material to another species - if the gene transferred is able to produce a counter measure against an antibiotic, then resistance spreads. There are other factors at play such as selective pressure - if an antibiotic is used on a population of bacteria, then any of these that mutate to be less sensitive will thrive and spread this advantageous mutation (by vertical gene transfer at first, but potentially also horizontal). Overuse and improper use of antibiotics all contribute to these issues.

An iChip being removed from the soil.

Now to the study. Hopefully I’ve made it clear that there is a pressing need for new antibiotics and have mentioned that if more bacterial species can be grown we have a better chance for discovery. A major source of bacteria (and our current antibiotics) has been soil, which is teeming with microorganisms. However, previously it had only been possible to grow roughly 1% of these in a laboratory setting. The team, led by Kim Lewis at Northeastern University in Boston, Massachusetts, set out to tackle this problem. The work took the highly inventive approach of growing soil bacteria in… wait for it… soil. There was a bit more to it than that of course. The team made use of a so called iChip, which is a device containing lots of tiny wells that bacteria can be grown in. Soil was collected and diluted so that 1 bacterial cell would end up in each well of the iChip, which was then placed in soil protected by semi-permeable membranes. These membranes allow nutrients to get to the bacteria in the iChip, but do not allow the bacteria to leave, or new ones to enter - thus allowing controlled growth of the bacterial cells plated into the iChip.
Using these iChips the group estimated that they were able to grow a remarkable 50% of bacteria that can be found in the soil, compared to the measly 1% that could be grown on a conventional Petri Dish. It was therefore possible to screen 10,000 new bacterial species (that had previously been described as 'uncultured') for novel antibiotic products using Staphoyloccus aureus (the bacteria that gives rise to MRSA). Again this was nice and simple; cultures of S. aureus were placed over each of the colonies of ‘uncultured’ bacteria and then analysed for death. 25 of the new bacteria were found to produce something capable of affecting S. aureus, the most potent of these being from a bacteria now known as Eleftheria terrae, which produce the compound teixobactin.

Analysis of teixobactin showed it to be a completely novel chemical structure for antibiotics, an exciting discovery. The compound was capable of killing many different strains of the class of bacteria known as Gram positive. Bacteria can largely be clumped into categories based on whether they can be stained by a chemical discovery by Hans Christian Gram. Many pathogenic bacteria are categorised as Gram positive, and were shown to be sensitive to teixobacin, such as M. tuberculosis (causes tuberculosis), C. difficile (causes infectious diarrhoea), B. anthracis (causes anthrax), and of course S. aureus. Indeed, the efficacy of teixobactin against S. aureus was demonstrated by infecting mice with a dose that would usually kill 90% of them - all of those that were then given teixobactin survived. Moreover, compared to vancomycin, the main treatment against MRSA, only a very small dose was needed for protection. A similar result was also seen in mice infected with S. pneumoniae, a bacteria that can cause pneumonia.

A diagram to show the different structure of Gram negative and positive bacteria
So what is this novel antibiotic doing? The group demonstrated that teixobactin acts in a very similar manner to vancomycin. Teixobactin can bind to two molecules used in the production of the bacterial cell wall, these being known as peptidoglycan and teichoic acid. Binding peptidoglycan causes disruption to the formation of the cell wall, causing the bacteria to die (the wall is essential for life). The binding of teichoic acid has a similar affect, but can also cause the release of molecules known as autolysins that further help to kill the bacteria. This function of binding components of the cell wall is the reason teixobactin only affects Gram positive bacteria; Gram negative bacteria are surrounded by a further outer membrane that hides their cell wall, and protects them from teixobactin. This outer membrane is also the reason Gram negative bacteria are negative - the Gram stain binds to peptidoglycan in the cell wall.

The fact that teixobactin binds to lipid molecules adds further excitement to this discovery. Genomes (ours, bacteria, animals, everything) carry genetic information for making proteins. As I mentioned, it is possible for bacteria to mutate and become resistant to antibiotics. This process involves changes to their genetic code, that result in changes to proteins. If proteins are targeted by antibiotics, then there is a good chance of resistance emerging. However, lipids are not produced by the genetic code so cannot be easily changed. Furthermore, the two lipids that are targeted by teixobactin are highly conserved in all bacteria. When this occurs in evolution, it is very strongly suggestive of the fact that they need to be exactly as they are, to the extent that if they changed, they would probably be useless. It is therefore believed that these lipids cannot be disposed of, or altered, making it very hard for bacteria to develop any resistance to teixobactin. Now you may be thinking, but what about the bacteria that produce teixobactin, surely they have mechanisms in place so they don’t get killed, that could spread by horizontal gene transfer. But here’s the final beauty in this discovery, E. terrae, that produce teixobactin, are a Gram negative species of bacteria. They are naturally immune to the actions of this new antibiotic so don’t need any direct mechanisms to counter it (and bacteria aren’t going to change from Gram positive to Gram negative). 

This is a very exciting discovery. However, it is not yet known whether teixobactin will work in humans, and even if it does, there will be a wait before it is available. It could take up to 10 years before the chemical reaches clinics. However, to have a new antibiotic in the pipeline is a timely discovery. Furthermore, the work from Kim Lewis’ team has opened a new avenue for discovery and growth of novel bacteria that may yield even more antibiotics. Optimistically, it looks like the simple idea of growing soil dwelling bacteria in soil may have opened the door for an exciting road to the discovery of new antibiotics.

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