Antibiotic/antimicrobial resistance already claims the lives of more than 2 million people per year in the United States, and experts warn that it could prompt a global economic crisis by 2050 if left unchecked.
Given the overuse of antibiotics in both human health and agriculture for the past 50 years, most scientists agree it is probably too late for the first generation of antibiotics.
“The challenge for humans now is to develop and protect the second generation of antibiotics,” Matt Hutchings, professor of molecular microbiology at the University of East Anglia (UK), told Laboratory Equipment.
The golden age of antibiotics was kick-started by the discovery and subsequent mass production of penicillin and streptomycin in the 1940s. It peaked in the mid-1950s, but by 1960 scientists were repeatedly rediscovering known antibiotics from soil microbes. So, pharmaceutical companies turned to their scientists to create synthetic versions of nature’s anti-infective molecules.
However, antibiotic-resistance keeps growing, putting more and more lives in danger. Subsequently, there has been a change of direction among some scientists that leads right back to nature.
“It is estimated there are more than 100,000 antibiotics waiting to be discovered from Streptomyces bacteria alone and—based on previous success rates—about 0.1 percent of these will make it through clinical trials,” explained Hutchings. “Most other bacteria and fungi make antibiotics as well, which means natural products are the best hope for discovering a second generation of antibiotics. Three billion years of bacterial evolution easily beats 10 or even 100 years of directed synthetic design.”
Plant and animal models
Hutchings lab is interested in how antibiotics are used in nature—by bacteria, animals and plants—and how they can exploit this to discover novel anti-infectives. For example, while the Streptomyces species is responsible for more than half of all known antibiotics, scientists know it has the capacity to make many more antibiotics than it produces in the lab. Most of its antibiotics are never made under lab-growth conditions, which is referred to as cryptic. Hutchings’ lab wants to find ways of switching on these cryptic pathways, and understanding the signaling networks that control antibiotic production in the bacteria is part of the equation.
Another part of the equation lies in the actions of the Acromyrmex and Atta genus, more commonly known as leafcutter ants. Leafcutter ants belong to the tribe attine, or fungus-growing ants. These ants actively cultivate their fungus, feeding it with freshly cut plant material and keeping it free from pests and molds. The fungus cultivated by the adults is used to feed the ant larvae, and the adult ants feed on leaf sap.
What’s even more unique about leafcutter ants is that they grow bacteria—in a symbiotic relationship—to protect their fungus. They grow it on the outside of their bodies, which allows Hutchings and his team to conduct easy experiments on their microbiomes, something that is a lot harder with other systems since bacteria is usually inside an organism. The goal of the experiments is to understand how plants and leafcutter ants control antibiotic production by their symbiotic bacteria.
“This is important because it may give us new ways to activate cryptic pathways,” said Hutchings. “It is also important to agriculture because if we can engineer better, more protective root microbiomes into food crops like wheat, rice and potato, we could increase yields and reduce the use of pesticides.”
The search
As the threat of drug-resistant infections increases, the race is on to find new microbes that could result in new drugs. Known as bioprospecting, scientists are searching near, far and wide for suitable candidates. Examples include:
- Marine sediment: In 1989, researchers from the Scripps Institution of Oceanography identified a new species of bacteria living in marine sediment, just off the coast of the Bahamas. Later to be known as Salinispora, strains of this genus have been found in tropical and subtropical seas around the world and have been found at depths of more than 5,000 meters. These bacteria are well adapted to their environment and only grow in the presence of seawater. Salinispora bacteria produce a compound called Salinosporamide A, which shows anticancer properties and is currently being tested in phase I clinical trials to test its effectiveness against two types of cancer cells.
- Marine sponges: Although they lack any obvious organs or limbs, marine sponges are some of the oldest animals on Earth. Sponges have been the source of anticancer drugs since the 1950s and thousands of other compounds have been derived from them. A great number of these potential drugs appear to be made by bacteria that live in mutually beneficial relationships with sponges across the world, including Salinispora and marine Streptomyces species. In the absence of an immune system, it is thought that these primitive animals use the antibiotic-producing bacteria to protect themselves against disease.
- The Atacama Desert: The Atacama might be the world’s oldest desert and is perhaps the driest place on Earth, with some areas receiving an average of 1 mm of rain a year. Although it was believed nothing could survive there, the desert has been shown to be home to new species of Streptomyces bacteria, including Streptomyces leeuwenhoekii, which produces new compounds called chaxamycins that have potent antibacterial properties.
- Soil: Far removed from the deserts of South America, garden soil remains an untapped source of potential new drugs. The majority of antibiotics in use today are made by members of the soil-dwelling Streptomyces genus of bacteria and many scientists believed there weren’t any left to find. However, the 2015 discovery of a new antibiotic compound called teixobactin—isolated from bacteria living in a grassy field—shows there might be more to find.
- Golf courses: Ivermectin is a drug that is used to treat a number of parasitic worm infections and has saved millions of lives. It cures diseases like river blindness, which disproportionally affect the poorest people on Earth. Ivermectin was derived from another compound called avermectin, produced by the bacterium Streptomyces avermitilis. The Japanese scientist Satoshi Omura isolated this species on the fringes of a golf course in Kawana, near Tokyo. As a result of his discovery, Omura was co-awarded the 2015 Nobel Prize in Physiology or Medicine.
- Your current surroundings: In addition to looking for new antibiotic-producing microbes in exotic places around the world, some are looking closer to home. Adam Roberts from University College London has been running a project called Swab and Send, which asks members of the public to swab a surface and send it to him to analyze for the presence of new antibiotic-producing bacteria. People have swabbed a huge range of places, and interesting microbial species have been found living on banknotes, train station ticket machines, a cat’s nose, the side of a fridge, and even men’s beards. The project is still in its early stages, but Roberts suggests the next antibiotic could be right under our noses—literally.
Challenges going forward
Attine ants have most likely been using natural product antibiotics for as long as they have been farming fungi—more than 50 million years. According to Hutchings, in addition to the bacteria they grown on their backs, attine ants can recruit additional actinomycete strains from the environment. These strains are usually associated with Streptomyces bacteria, which suggests attine ants use multiple antibiotics from a mixture of actinomycete strains to prevent drug resistance arising in the microbes that infect their fungus gardens.
“Plants and animals have been using antibiotics for millions of years, possibly even hundreds of millions of years, and they still seem to be effective,” Hutchings said, “whereas, in less than 100 years, [humans] have misused antibiotics so badly that most of them aren’t effective at treating disease anymore.”
Now, a challenge for the U.S.—and the rest of the world—is changing the culture that surrounds antibiotics. Moving the needle from a mediation that is prescribed in excess, to one that is only offered in the case of a life-threatening infection.
“The remaining question is how to fund antibiotic discovery and development in the future” said Hutchings. “These are life-saving drugs that aren’t highly valued by society. They are sold too cheaply. Lifestyle and anti-cancer drugs are a lot more profitable.
“So, the first challenge will be deciding who is going to fund the discovery and development work and the second will be controlling the use of new antibiotics. Ideally, we want governments to stockpile new antibiotics and never use them unless there is a life-threatening outbreak of disease,” Hutchings concluded.