Inside the Search for New Antibiotics
With no new viable antibiotics produced in over a decade, scientists are getting more creative with their methods.
You might not think that the crud stuck to the bottom of your shoe or the grime on the knees of the neighbor’s kid or the mud clinging to an alfalfa root could contain anything that might save your life. But many of today’s drug hunters are turning to the ground beneath our feet — and our toilet seats, subway platforms and other dirty places — to uncover some of medicine’s most critical fighters of infection: antibiotics.
We’ve long known that soil teems with a diversity of microbes, and these organisms compete for nutrients by releasing compounds that can kill their rivals. It turns out many of these compounds make great medicines. Penicillin, for example, came from Penicillium, a fungus that lives in soil. Vancomycin, which is used to treat staph infections, is produced by Streptomyces orientalis, a bacterium found in dirt. During what many refer to as the golden age of antibiotic discovery between the 1940s and 1960s, pharmaceutical companies enlisted Christian missionaries, explorers, pilots and foreign correspondents to collect soil samples from distant corners of the earth for screening in their labs.
For a couple of generations, the antibiotics they collected worked miracles, preventing simple scratches or surgical incisions from developing infections that might otherwise have served as death sentences. But these drugs worked so well that hospitals, clinics and farmers began to overuse them, which led to resistance and created so-called superbugs, microbes that are resistant to multiple drugs, setting off an urgent healthcare crisis. Now infections that don’t respond to antibiotics kill 700,000 people around the world every year, a number some researchers worry could climb to 10 million by 2050.
No new viable antibiotics have been produced in over a decade, and for forty years, the consensus has been that the dirt is tapped out. At the end of that golden age of discovery, the pharmaceutical companies began to rediscover the same antibiotic compounds over and over again. But the new drug hunters are tweaking the old screening methods and using brand new ones, and applying new technologies. They are also turning to crowdsourcing and citizen science to maximize the amount of dirt they can haul into their labs, to educate the public, and to teach the next generation of scientists about antibiotic development. Below are five sets of scientists who are digging through the dirt with some success.
The RNA Interruptors: Rutgers University / NAICONS
Some of our newest antibiotics could potentially emerge from a clump of dirt that was collected beneath a Cypress tree in Tuscany some time in the late 20th century. In June of 2017, scientists from Rutgers University and the New Anti-Infectives Consortium (NAICONS) in Italy published research in Cell that identified a promising compound from that soil by using new tricks to look for as-yet undiscovered antibiotic compounds.
Antibiotic discovery has traditionally involved growing bacteria found in dirt in petri dishes, isolating the specific compounds produced by that bacteria and then testing their killing power against specific pathogens, such as Escherichia coli, or E. coli. This is called the Waksman technique and yielded many of our first soil-derived antibiotics. But while the technique is really good at finding antimicrobial compounds that are present in high concentrations, it misses potent but low abundance molecules that if made in a lab might make great antibiotics. So the Rutgers-NAICONS team, led by Richard Ebright, Laboratory Director at the Waksman Institute of Microbiology of Rutgers University, tried something different.
They searched Lepetit Pharma’s library of 3,000 compounds produced by bacteria and fungi, compounds isolated decades ago, for ones that interrupt RNA synthesis — but only in bacterial cells, not human ones. (If it interrupted RNA synthesis in humans, it’d be a mighty dangerous drug to take.) The most promising of the compounds Ebright’s team found is called pseudouridimycin, PUM for short, which kills a broad spectrum of bacteria in lab cultures, including drug-resistant ones, and cures bacterial infections in mice. PUM and other compounds they have found are in various stages of research.
“It’s extremely easy to find new antibiotics, as long as you don’t use the same methods for looking for them,” says Ebright.
The 99%: Northeastern University
“We know more about the movement of celestial bodies than about the soil underfoot,” Leonardo Da Vinci once observed. And that remains largely true 500 years later, at least when it comes to the bacteria that thrive there. Some 99% of bacteria found in soil tends to die off as soon as it is transferred to a lab culture, which makes it very difficult to study. But a tiny new plastic tool, designed by scientists at Northeastern University, allows researchers to culture bacteria in the soil itself, opening up a whole new universe of bacteria and possible antibiotics to research.
Dubbed the iChip, for isolation chip, the two-and-a-half inch long chamber contains a slurry full of nutrients and has 306 tiny indentations in its surface each big enough for a single microbe. When the chamber is placed in a tub of dirt, bacteria that otherwise expire in lab culture begin to form colonies in their native environment. Many of these colonies are then strong enough for survival in the lab.
In 2015, the Northeastern University team used the iChip to isolate a promising compound called teixobactin from German dirt. Teixobactin kills the bacteria that cause pneumonia, staph, and blood infections in mice.
Student-Sourcing: Small World Initiative / University of Wisconsin
Jo Handelsman, a microbiologist at the University of Wisconsin, believes that sheer numbers combined with academic rigor will work in her favor. She runs the Small World Initiative, launched in 2012, which uses soil collection and antibiotic discovery to teach basic microbiology to 10,000 high-school and college students around the world each year. “I call it student sourcing, actually,” she says. “Using students as the crowd, which gives it a much more rigorous base.” The program has an established curriculum, a training program for instructors and big ambitions. Over the next few years, Handelsman wants to raise the number of enrolled students to 100,000 and to build a chemistry lab that can determine whether the compounds found to be active against selected pathogens are really new antibiotics.
“We have such large numbers, that even one percent of, say 100,000 extracts, is not a bad discovery rate,” she says. One of the most exciting and useful discoveries the students have made so far, she says, is that growing bacteria on a potato-based medium may yields more antibiotic-producing bacteria, something her lab is currently working to confirm through its own research.
Dirty DNA: Drugs from Dirt / Rockefeller University
During the golden age of antibiotic discovery, whole genome sequencing technology wasn’t available to science. Today, the genomic sequences of over 30,000 bacteria are publicly available. Scientists have also identified genes associated with certain families of metabolites , such as polyketides and non-ribosomal peptides, that are essential in the production of the vast majority of antibiotics, not to mention many microbe-derived anti-cancer agents, immunosuppressants and anti-fungals, explains Sean Brady, a professor at Rockefeller University in New York, who runs a project called Drugs from Dirt. By looking for these genes that are responsible for these metabolites , the project aims to identify novel compounds that act like antibiotics in spoonfuls of dirt.
The project has already collected dirt from every continent and a diversity of biomes that include rainforests, temperate forests, deserts and coastal sediments, as well as a number of islands. These days the collection efforts emphasize large-scale collaborations with academics in foreign countries. Brady is also aiming to collect soil samples from every state in the U.S. through a crowdsourcing campaign. So far, Brady and his team have identified a handful of compounds that have potentially promising antibiotic potential. The next step is to test them in animal models.
Everyday Crud: Swab and Send / Liverpool School of Tropical Medicine
So far over a thousand swabs have been mailed in to a third crowdsourcing campaign called Swab and Send, including samples from a pig trough, a piano keyboard, the SS Great Britain in Bristol. English microbiologist Adam Roberts, who runs the Swab and Send program, is hoping to identify new antibiotics in these overlooked bits of dirt. The program, which has an active Facebook page, seeks citizen scientists to collect dirt from their everyday environments using cotton swabs sent by mail. Roberts has so far identified almost six thousand different kinds of bacteria that he and his team are testing in the lab to see if they can kill multi-drug resistant E-coli and Candida albicans, among other bugs.
The Swab and Send program has just moved to the Liverpool School of Tropical Medicine, which means access to a lab of chemists who can determine whether the antibacterial compounds identified in these screens are novel or old news. Roberts says he’s not just looking for antibacterial compounds, but antimalarial and other antiparasitic compounds . He’s also hunting for compounds that can kill biofilms — multi-species bacterial communities like the ones found in plaque on your teeth.
“If I’ve got samples coming in from all over the world, that’s quicker than me just going out and finding them, and the diversity is increased,” says Roberts. But he also wanted to engage the public, so that the message around antibiotics and superbugs isn’t all doom and gloom. “I want people to use their imaginations,” he says.
And they do. Roberts says his citizen scientists have sent in samples labeled, “tiger” and “seagull feet.” And yet, some of the hottest spots for antibiotic activity may still be found in the most mundane of places: Rockefeller University’s Sean Brady says that though he has collected spoonfuls of dirt from all over the world, his parents’ backyard in New Mexico has so far turned out to be one of the richest for promising finds. At least our modern day drug hunters will not lack for dirt and grime to dig up.
More on antibiotic resistance below:
I Contain Multitudes is a multi-part video series dedicated to exploring the wonderful, hidden world of the microbiome. The series is hosted by science writer Ed Yong and produced by HHMI Tangled Bank Studios in association with Room 608.
