Since 1939, when René Dubos, a researcher at Rockefeller University, smeared dirt across a petri plate and isolated the antibiotic gramicidin, the search for antibiotics has largely been culture-dependent. It is limited to the finite percentage of bacteria and fungi that grow in the laboratory. If the chance of finding a new antibiotic in a random soil screen was once one in 20,000, by some estimates, the odds have dwindled to less than one in a billion now. All the easy ones have already been found. But that doesn’t discourage Sean Brady, head of the Laboratory of Genetically Encoded Small Molecules at the Rockefeller University in New York, who scours Central Park, looking for drugs. Brady is creating drugs from dirt. He is certain that the world’s topsoils contain incredible, practically inexhaustible reservoirs of undiscovered antibiotics, the chemical weapons bacteria use to fend off other microorganisms. He’s not alone in this thinking, but the problem is that the vast majority of bacteria can’t be grown in the lab—a necessary step in cultivating antibiotics. Brady has found a way around this roadblock, which opens the door to all those untapped bacteria that live in dirt. By cloning DNA out of a kind of bacteria-laden mud soup, and reinstalling these foreign gene sequences into microorganisms that can be grown in the lab, he’s devised a method for discovering antibiotics that could soon treat infectious diseases and fight drug-resistant superbugs. In early 2016, Brady launched a company called Lodo Therapeutics to scale up the production and ultimately help humanity outrun infectious diseases nipping them at the heel. His lab recently dispatched two groups of student volunteers to collect bags full of dirt at 275 locations around New York City. Lodo’s bioinformatics team uses algorithms to predict which fragments in which libraries are likely to synthesise which molecules, so that, in the end, the robot recovers the ones with the gene clusters needed to create antibiotic molecules.
In 2015, Rockefeller University scientists had analysed soils from beaches, forests, and deserts on five continents and discovered the best places in the world to mine untapped antibiotic and anti-cancer drugs. The findings, published in the open-access journal eLife, provided new insights into the natural world, as well as a roadmap for future drug discovery. The vast majority of antibiotics in clinical use today are derived from soil bacteria, but the yield of new drugs is low because the same cultivated bacteria, and the set of molecules they synthesise, are repeatedly rediscovered. However, for every cultured bacterial species, there are 100 uncultivated species in the environment. Scientists have previously identified clusters of bacterial genes that are particularly good at producing therapeutics. This knowledge meant the scientists could focus on searching for certain types of gene clusters in samples rather than having to sequence and analyse the whole genomes of bacteria. The team compared environmentally-derived DNA to DNA from laboratory-grown bacteria chosen for their ability to make more than 400 natural product compounds. The analysis revealed soils particularly rich in important gene clusters.
The routine use of antibiotics and the reckless misuse in humans and animals accelerates resistance. But despite technological advances in robotics and chemical synthesis, researchers kept rediscovering many of the same easy-to-isolate antibiotics, earning the old-school method, which earned itself a derisive nickname: “grind and find”. That’s why Brady and others turned to metagenomics—the study of all the genetic information extracted from a given environment. The technique originated in the late 1980s when microbiologists began cloning DNA directly out of seawater and soil. Using high-throughput DNA sequencing, scientists then searched these libraries and their census turned up such astronomical biodiversity that they began adding new branches to the tree of life. By some estimates, the earth harbours more than a trillion individual microbe species. A single gram of soil alone can contain 3,000 bacterial species, each with an average of four million base pairs of DNA spooled around a single circular chromosome. The next steps followed a simple logic: find novel genetic diversity, and you’ll inevitably turn up new chemical diversity.
Taking a novel drug through clinical testing and human trials takes, on average, about 10 years and several billion dollars. At best one in five new drugs succeeds, and so the financial rewards are mismatched with the immense value antibiotics provide to society. Some of this comes down to the drug’s nature and activity: the more we use antibiotics, the less effective they become; the more selective pressures we apply, the more likely resistant strains will emerge. And so antibiotics used to treat the deadliest pathogens are kept as a last resort when all else fails, such as the carbapenems. Gravely ill patients taking last-line antibiotics can end up dead or they can end up cured; either way, they’re not repeat customers, which, over the long term, adds up to a negligible or negative return on investment. In recent years, researchers have been trying to reinvigorate antibiotic discovery in several ways. A team from Northeastern University developed a specialised plastic chip that allowed them to culture a broader diversity of bacteria in the field, which led to the discovery of teixobactin from a meadow in Maine.