Microbes that inhabit the human body make a treasure trove of small molecules that could be developed into drugs such as antibiotics, chemotherapy, cholesterol-fighters and other therapies, a new study reveals.
An analysis of 2,430 bacterial genomes isolated from a wide range of body sites shows that people’s bacteria are capable of making some 44,000 different small molecules, researchers report September 11 in Cell. Small molecules have been shown to be important for communication between bacteria and their hosts. Also, many drugs are small molecules.
“Many [microbes] can make drugs like those we’re already taking or evaluating in clinical trials,” says study coauthor Mohamed Donia, a biochemist who recently moved from the University of California, San Francisco to Princeton University. One of the drug candidates Donia and his colleagues discovered is a new antibiotic produced by vaginal bacteria to fight off pathogens.
This new work is a tour de force that mines genetic data to uncover a wealth of new chemicals that may help shape human health, says Harvard University microbiologist John Mekalanos.
Most previous studies of people’s resident microbes, known collectively as the microbiome, have focused on which bacteria inhabit particular body sites or how microbe mixes change with diet or disease. The new study delves much deeper to give a fuller picture of how microbes interact with each other and with their human hosts, Mekalanos says.
“They really have uncovered the iceberg under the water,” he says.
In the study, researchers combed publically available data to find genes involved in synthesizing small druglike molecules. The data came from the Human Microbiome Project and other databases containing “every single genome from every single bug isolated from humans,” Donia says.
In bacteria, genes involved in particular biochemical chain reactions usually cluster together in the genome. These “biosynthetic gene clusters” encode enzymes, each of which carries out one biochemical reaction to build a particular molecule, such as a sugar or antibiotic.
A typical human mouth contains 1,061 gene clusters capable of making at least that many different molecules, the researchers discovered. Typical human guts have 599 gene clusters. Bacterial communities on the skin, in the airways and in the urogenital tract contain fewer gene clusters.
Bacteria use these small molecules to manipulate their environment, says Peter Dorrestein, a chemical biologist at the University of California, San Diego, who studies the function of microbial products. Some molecules, such as the vaginal antibiotic discovered in the study, are part of the ongoing chemical war between bacteria.
Other molecules, such as the hundreds of sugars called saccharides made by gut bacteria, may interact with human’s immune system proteins to fuel or calm inflammation, or pave the way for a particular bacterium to settle into a niche. Dorrestein predicts researchers will find that fungi make a plethora of manipulative molecules, too.
The majority of the gene clusters found in human-dwelling bacteria — 30,000 — have no known function. “It’s the stuff of bioscience fiction to imagine what all these things are doing,” Mekalanos says. For example, obese people’s microbes may make antibiotics that kill off bacteria that keep people lean. And instead of just killing rival bacterial, antibiotics from microbes may do double duty and also help their producers communicate with their human hosts, he speculates.
The newly discovered antibiotic, lactocillin, is a type of molecule called a thiopeptide. A similar molecule is in human tests for treating intestinal infections with Clostridium difficile. A bacterium called Lactobacillus gasseri makes lactocillin in the vagina and some bacteria in the mouth also make the antibiotic. Other bacteria throughout the body produce their own thiopeptide antibiotics, the researchers found.
Now that researchers have discovered the microbial molecules, some that bacteria have used to fight each other may one day be engineered to kill only harmful bacteria. Or doctors could give people microbes that make antibiotics in order to reshape their microbiomes into healthier communities, Donia says.
He and his colleagues are making all of their data publically available in the hope that other researchers will discover the functions of other molecules. With more than 40,000 unexplored molecules produced by the gene clusters, Donia says, “We’re not going to be able to do this alone.”
