The incredible journey
26 Sep 2013 by Evoluted New Media
The cuticle of a leaf cutter ant and the Atacama Desert – the race to find new antimicrobial drugs is taking scientists to some truly surprising places
We are facing a crisis in health and wellbeing, one that could take us back to the bad old days where a simple wound, a routine operation, or a winter chest infection was a serious threat to life. This threat comes from the simple fact that very few new antibiotics have been developed during the past 20 years and those that are available are being overcome by the relentless evolution of pathogenic microbes.
The race is most definitely on to find new effective and tenacious antimicrobial drugs. And it’s taking scientists to some quite peculiar places.
From the discovery of penicillin in a bread mould, microorganisms have inspired a range of antibiotics. And now it’s those microorganisms living in extreme and unusual environments that we turn to.
Extremophiles that exist in the least explored corners of our planet have already proven a rich source of biological products, from the DNA polymerases used in the laboratory for PCR, to food additives and dietary supplements. It’s perhaps not surprising then to find out that bacteria living in deep sea thermal vents, salt lakes, or desert soils are a rich source of new avenues of drug development. But perhaps more surprising are the lessons we can learn from the leaf cutter ant.
Leaf cutter ants are prolific gardeners of fungi. They collect vegetation, which is broken down inside their vast convoluted nests to feed the growing beds of fungus that provide the main food source for the ants. But it’s not the fungi that is most interesting for drug discovery, in fact, it’s the way in which leaf cutter ants have managed pathogenic microorganisms for the health and wellbeing of the colony.
A population of symbiotic bacteria live on the outer cuticle layer of the leaf cutter ant’s hardened exoskeleton. These bacteria produce antibiotic compounds that in turn protect the ants from pathogens. It is testimony to the success of this relationship that the ants have enjoyed 50 million years without a superbug whereas humans have been using antibiotics for less than 100 years and we are facing a crisis; we could perhaps learn something about good antibiotic stewardship from the leaf cutter ant.
As the ants grow, they acquire more and more strains of bacteria that produce a range of antibiotics. In effect, they are applying a multidrug therapy approach, which has so far protected them from any problem with drug resistance.
It doesn’t stop with antibiotics, though, it turns out the ants may also be harbouring the next generation of cancer treatments.
Whilst investigating antibiotic compounds from leaf cutter ant symbiotic Streptomyces bacteria, Dr Matthew Hutchings and colleagues at the University of East Anglia stumbled upon the possibility that there might also be powerful anti-cancer drugs lurking in amongst the possible compounds. They are now developing a new class of chemotherapy products that are not only powerful but also circumvent a primary cause of resistance to chemotherapy, attendees at the Society for Applied Microbiology Summer Conference heard on 3 July 2013.
There are over 40 antimycin compounds produced by the symbiotic bacteria living on leaf cutter ants but until recently the synthetic pathways had not been investigated. Dr Hutchings team is cloning as many gene clusters as possible in order to find the enzymes involved in antimycin production. They have identified two pathways so far.
Antimycins have two modes of action against microorganisms. Firstly, they disrupt oxidative phosphorylation – a critical part of energy metabolism. Secondly, they inhibit proteins that prevent apoptosis. These activities present both challenges and opportunities. The metabolic disruption means that antimycins are extremely toxic to most cells. But their ability to promote apoptosis has piqued interest.
Resistant cancers have been found to produce much higher levels of proteins that prevent apoptosis. The ability of antimycins to inhibit these proteins and enable apoptosis to continue as intended has the potential to make a huge difference in clinical outcomes.
The challenge of overcoming toxicity of antimycins is where Dr Hutchings and his team come in. Work by organic chemists has shown that antimycins can be altered to reduce their impact on oxidative phosphorylation and also promote the inhibition of anti-apoptosis proteins. But to produce significant quantities of altered antimycins by organic chemistry would not be a viable option.
Dr Hutchings said “We’re using genetics to understand how the drugs are made in the bacteria so we can tweak the characteristics in favour of anti-cancer action, whilst protecting healthy cells. We want to make Streptomyces into a factory to produce this new type of chemotherapy drug on a large scale.”
Dr Hutchings’ team aim to make these changes through genetics so that the drugs can be made cheaply and on a large scale using bacteria in fermentation tanks.
Meanwhile, at Newcastle University, Professor Michael Goodfellow has been screening bacteria from the oldest and driest desert in the world for potential antibiotics.
Professor Goodfellow is interested in actinobacteria, which are found almost anywhere with any vague potential to harbour life; this includes the Atacama Desert. Working on desert soils, new species of actinobacteria have been discovered and within these are a great number of potential bioactive compounds.
The challenge now is to screen compounds from bacteria found in desert soils, deep sea muds, and other extreme environments for potential medical applications. There are two potential difficulties, though. Firstly, to culture these bacteria is not straightforward and a large proportion of research effort is given over to being able to work with them in a laboratory environment. Secondly, screening takes time and could have the potential to rediscover already known chemical entities.
Professor Goodfellow is approaching some of the difficulties posed by pursuing new techniques in predictive and integrative biology. Candidate actinobacteria strains are being selected now for genome mining and systems biology and synthetic biology approaches.
So, it’s not all bad news. But it will be vital to tackle antibiotic resistance from a number of angles.
As well as the search for new antimicrobials in unusual places, and other paths to drug discovery, we need better prescribing policies and improved hygiene. And, critically, antibiotics should only ever be used when there is a defined need.
Monitoring on local and global scales will help to maintain good antibiotic stewardship in human and animal healthcare. And understanding the biology behind the evolution of bacterial resistance in a variety of scenarios continues to be an important aim of research.
Author: Nancy W Mendoza, Communications at Society for Applied Microbiology
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