The search for a new antibiotic

The iChip device, developed by scientists at Northeastern University, Boston, allows bacteria to grow in its natural environment but to be isolated and studied at the same time. Slava Epstein / Northeastern University
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Scientists have made a breakthrough in their search for a new generation of antibiotics. By studying bacteria in the soil they believe they can develop medicines that will combat the menace of drug-resistant superbugs.

The solution to what the World Health Organisation describes as a “profound threat to human health” could lie at the bottom of your garden or in a muddy field.

Buried in the dirt are thousands of compounds that could bring an end to “superbugs” – the illnesses that no longer respond to most antibiotics.

Scientists at Northeastern University in Boston, US, announced a breakthrough last month, in that they have worked out a way of cultivating bacteria that until now has failed to grow in laboratory conditions, but which could be the source of a new generation of antibiotics. Naturally occuring micro-organisms and bacteria are the main source of antibiotics used today.

In the heyday of antibiotic discovery between the 1930s and 1970s, scientists could only study about one per cent of the bacteria found in soil samples because the other 99 per cent would not grow outside their natural environment. This made the discovery of antibiotics a difficult, costly and lengthy exercise.

“Overmining of this limited resource by the 1960s brought an end to the initial era of antibiotic discovery,” said Northeastern University’s Kim Lewis, Slava Epstein and others, in their research paper published in Nature magazine.

No new major forms of antibiotics have been developed in the past 30 years, and resistance to certain types has been growing.

The latest breakthrough in growing bacteria in the lab could unlock a huge source of as-yet untapped antibiotics.

The success lies in the development of a technology called iChip, which allows bacteria to grow in soil, their natural environment, and to be isolated and studied at the same time.

iChip involves diluting a sample mixture of soil so that one bacterial cell is placed between two laboratory slides and put back in the soil.

The scientists estimate that almost half of samples will grow using this method, as compared to just 1 per cent of cells from soil that would grow in a lab.

In this experiment the team, consisting of Lewis, Epstein and colleagues from the Uni­ver­sity of Bonn in Ger­many, Selcia in the UK and Novo­Bi­otic Phar­ma­ceu­ti­cals in Cambridge, Massachusetts, then screened 10,000 samples grown in iChips for antimicrobial activity on Staphylococcus aureus, the resistant form of which is known as MRSA.

A newly discovered compound that the team named teixobactin has already shown promise against resistant forms of bacteria such as S.aureus and Mycobacterium tuberculosis.

It was also “exceptionally active” against non-resistant Clostridium difficile, which causes infectious diarrhoea, and Bacillus anthracis, the anthrax bacteria.

Dr Anjam Khan, principal investigator and director of the Microbiology Containment Level 3 Research Suites at Newcastle University, UK, said: “The good thing about this announcement isn’t so much the antibiotic but the approach the investigators used to try to cultivate bacterial dark matter.

“Scientists have always tried to mimic environmental conditions in an artificial laboratory growth medium rather than going back to the soil.

“The strategy these scientists have used is very elegant. They devised a new experimental tool where they could look at individual bacteria growing in their natural soil environment.

“Most antibiotics we get are from soil-dwelling bacteria, yet we are missing 99 per cent of this diverse and rich population of bacteria which we simply cannot cultivate in artificial laboratory media.

“The technology is very simple. That’s one of the elegant and powerful things about this approach.”

He said scientists had been trying for many years to grow bacteria in a laboratory, and it had been a “guessing game” as to what nutrients were needed to ensure growth.

“It gives us a glimmer of hope,” he said. “It’s probably really the first report of a brand new antibiotic. It has a double edge to it. Firstly, it’s effective against Gram-positive superbugs, and secondly, its target is less vulnerable to mutation and change than previous antibiotic targets.”

As well as the success of cultivating bacteria, the research team was also excited to report that the new antibiotic compound was effective against resistant bacteria.

Lewis said it marked the first discovery of an antibiotic “to which resistance by mutations of pathogens have not been identified”.

“Our impression is that nature produced a compound that evolved to be free of resistance,” he said.

“This challenges the dogma that we’ve operated under, that bacteria will always develop resistance. Well, maybe not in this case.”

Improper use of antibiotics is the main cause of resistance. Taking them unnecessarily or incorrectly, by not following instructions or failing to complete a course, gives bacteria the chance to develop resistance.

Last year, the WHO said antibiotic resistance posed a serious threat to the public as the world headed towards a “post-antibiotic era”.

Dr Keiji Fukuda, WHO assistant director general, said: “A post-antibiotic era in which common infections and minor injuries can kill, far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century.”

Common infections prevalent in intensive-care and neonatal units were becoming very difficult or impossible to treat, the WHO warned, and the pipeline for the development of new antibacterial drugs was “virtually empty”.

With the creation of iChip and the discovery of teixobactin, this could be about to change.

Even the way teixobactin operates is a source of hope in itself.

It targets the bacteria cell walls, rather than attacking bacteria proteins like most other antibiotics. The latter gives the bacteria a much greater opportunity to develop resistance.

The scientists estimated it would take bacteria more than 30 years to become resistant.

Dr Khan pointed out, however, that it could also take a decade for an antibiotic to reach the market and cost more than US$1 billion [Dh3.7bn] to do so.

“It has been tested in-vitro [an artificial environment] and in mice, but it still hasn’t been tested in humans. It’s quite possible that in humans you might get side reactions. You can’t relate too much from small animals such as mice. You have to do clinical trials. I do think there is some hype surrounding this drug; some of it is well placed and other parts are a bit too optimistic. But it is a glimmer light at the end of the tunnel.”

Dr Khan and another scientist from Durham University in the UK, Adrian Walmsley, recently submitted their own funding grant to work on an antibiotic research project.

Their work will examine an alternative strategy to tackle bacterial infections by targeting a mechanism in the bacteria which triggers changes in genetic coding and develops resistance.

“This is an attractive approach since it would restore the effectiveness of many antibiotics that have fallen out of use; these compounds of course have passed the regulatory hurdles and could immediately be re-employed,” said Dr Khan.

There is also more work to be done to identify new compounds that, unlike teixobactin, target Gram-negative bacteria which causes bugs such as salmonella, E. coli and cholera.

Hosam Zowawi, a clinical microbiologist based at the University of Queensland, Australia, and originally from Saudi Arabia, said soil was a “gold mine” of possible antibiotics, but that scientists still needed to explore other arenas, particularly to find antibiotics to work against Gram-negative bacterias.

“Gram-negative bacteria are mostly the bugs that cause hospital-acquired infections or community-acquired urinary tract infections. They are very, very prevalent, particularly in the Gulf. They can’t be killed with this new antibiotic. Having it available is great, but we need something to target Gram-negative.”

In May last year, scientists from The Rockefeller University in New York launched the Drugs From Dirt website to help find compounds in soil that could be turned into antibiotics.

The website says DNA from the soil can be sequenced to identify “genes of interest” that could “guide the discovery of new antibiotic compounds”. It calls on the public to collect samples from all 50 American states, and then from around the world.

“Take a sandwich bag, a spoon or a trowel, and dump a couple of spoonfuls in the bag and ship it to us,” said Dr Sean Brady, head of the Laboratory of Genetically Encoded Small Molecules at the university.

The WHO is preparing to present its global action plan to combat antimicrobial resistance, at the 68th World Health Assembly in Geneva, in May. It sets out five objectives: to improve awareness; to improve surveillance and research; to reduce infections; to optimise the use of antimicrobial agents; and to develop sustainable investment.