by Wei Li
figures by Rebecca Senft
If you’ve ever taken an organic chemistry class, you may know that making chemical compounds can be a long and painful process. Bacteria, however, face no such struggles. After millions of years, these tiny microbes have evolved into the perfect molecule-makers — powerful factories capable of churning out many complex molecules. These molecules are known as bacterial natural products, and they are surprisingly pervasive in our lives.
What are natural products?
Every living organism is able to produce molecules known as primary metabolites that are essential for growth, development, or reproduction. Amino acids, the building block of proteins in our bodies, are important examples of primary metabolites. Certain organisms, like plants, fungi and bacteria, are able to make another class of molecules that we call secondary metabolites, or natural products. As opposed to primary metabolites, secondary metabolites or natural products do not have a direct role in the organism’s normal growth or reproduction; removing these molecules from the organism does not result in immediate death.
So what is the purpose of natural products? Why do plants, fungi and bacteria even make them? The answer is because, unlike humans and animals, these organisms do not have the ability to run away from predators or other dangers. In order to survive in an oftentimes harsh environment, they rely on natural products that are designed for specific tasks that can help them survive in their ecosystem, such as protection against other organisms or interaction with their own species (Fig. 1).
Because these molecules are made to have an effect on other organisms in various ways, they can be very useful as therapeutics. For example, they can be used to kill harmful bacteria infecting humans, or even have an effect directly on human cells for various therapeutic purposes. In fact, most of our medicines are actually derived from or inspired by natural products.
The remarkable history of bacterial natural products
One important use of natural products is antibiotics. Ever since the serendipitous discovery of penicillin in 1928, which was a natural product from fungi that could kill bacteria, the scientific community rushed to explore other natural products that could also be used as antibacterial drugs. Specifically, they focused on natural products from bacteria, or bacterial natural products, because microbes often pump out molecules that can kill other microorganisms in the environment in an attempt to outcompete one another. Thus, such natural products were thought to be especially great resources for finding potential antibiotics.
Indeed, through the study of natural products produced by soil bacteria, scientists ushered in what we now call the golden age of antibiotic discovery. From the 1940s to the 1960s, there was a dramatic increase in the number of antibiotics on the market. Common antibiotics such as streptomycin, tetracycline, vancomycin, and erythromycin, were all natural products found from bacteria. Since their discovery, they have been a major part of our arsenal against deadly infections, greatly improving our ability to treat infectious diseases. (Of course, with the rise of antibiotic resistance, these drugs are no longer sufficient, but that is a discussion for another day…).
In addition to antibiotics, many bacterial natural products have other therapeutic uses. For example, rapamycin, also known as sirolimus, is made by the bacteria Streptomyces hygroscopicus, and is used clinically as an immunosuppressant, especially during a kidney transplant. Bleomycin, a natural product found from Streptomyces verticillus, is a chemotherapy drug used in the treatment for a range of cancers.
If these molecules are so powerful, why aren’t scientists focusing all of their energy on finding more bacterial natural products that could be used as drugs? This is because, after the glorious golden age of drug discovery, they hit a roadblock — efforts to find new bacterial natural products no longer derived new compounds; instead, there was a constant “re-discovery” of known molecules that were already on the market. The lowest hanging fruits have all been picked, and now, much more effort is required to reach for the rest.
But before we talk about what we can do to find more bacterial natural products, we should first understand how natural products are made in bacteria.
How Do Bacteria Make Natural Products?
It turns out that calling bacteria a molecule-making factory is not too far from the truth: many bacterial natural products are made in a way that is very similar to an assembly line.
In a factory, each worker will add parts to a product before moving the semi-finished product to the next factory worker, and this goes on until the final assembled product is produced. Instead of factory workers, bacteria have enzymes: proteins that catalyze, or speed up, chemical reactions. These enzymes work together in a manner similar to factory workers; some enzymes are tasked with putting on a certain building block, thus “building” up the molecule, while others take the resulting chain of building blocks and rearrange them to form the final compound (Figure 2).
The genes in the bacteria that encode for each of these enzymes are typically lined up side-by-side. We call these genes Biosynthetic Gene Cluster (BGC) — a cluster of genes that are responsible for making these important enzymes and thus the natural products. Therefore, we can look for bacterial natural products by looking for these BGCs in the bacteria’s DNA.
How can we discover more natural products?
There are many avenues that scientists are exploring in search of novel bacterial natural products. For example, with the recent improvements in sequencing technologies, scientists can now sequence the genomes of their bacteria of interest, and then use computers to search through the DNA sequences and predict possible BGCs. They can then run further experiments with the predicted BGCs to find out more about the natural products that are being made by the microbes. Furthermore, advancements in gene editing tools, such as the CRISPR/Cas9 technology that was awarded the 2020 Nobel Prize in Chemistry, can enable scientists to modify the genomes of bacteria and mutate the BGCs to make new “unnatural” natural products. For example, in a study published in 2018, scientists mutated the BGCs by removing, modifying, or reorganizing various parts of the assembly line, generating a whole range of unique and interesting molecules.
Recently, many scientists are also searching for novel bacterial natural products by looking in other environments. Beyond soil bacteria that dominated the natural products discovery research, there are also bacteria inside humans (in our gut and oral microbiome), and other animals. Many natural products identified in the gut microbiome have been proven effective as “narrow-spectrum” antibiotics: antibiotics that only kill a certain species of bacteria. For example, Ruminococcin C is a natural product isolated from a human gut bacteria, Ruminococcus gnavus, that can specifically target the harmful bacteria Clostridium perfringens. These environments have not been explored as extensively as soil, and thus can be potential gold mines for promising bacterial natural products.
Bacteria — tiny but powerful machines
Bacteria are indeed one of nature’s best molecule-making machines, providing us a huge arsenal of modern-day drugs. Through millions of years of evolution and exchanging genes between one another, these tiny microbes are poised to make unique and complex molecules that can have many useful properties.
Nowadays, pharmaceutical companies have moved away from natural product discovery towards other drug discovery approaches (e.g. high-throughput screening, where millions of existing small molecules are screened for their potential therapeutic effects). However, we should not abandon bacteria and their brilliant factory. There is definitely still a huge reservoir of bacterial natural products that we have not yet discovered, and with improving technologies in sequencing and bioengineering, we can certainly uncover them from bacteria.
Wei Li is a third-year Ph.D. student in the Chemistry and Chemical Biology program at Harvard University.
Rebecca Senft is a fifth-year Program in Neuroscience Ph.D. student at Harvard University who studies the circuitry and function of serotonin neurons in the mouse.