How scientists discover bioactive natural products from microbes to develop life-saving medicines
Imagine a universe of constant chemical warfare, where untold billions of tiny organisms are locked in a silent, invisible battle for survival. They can't run or hide, so they fight with chemistry.
This is the world of microbes—a realm of bacteria and fungi so small that millions can fit on the head of a pin. And in this microscopic arms race, these organisms have become master chemists, producing an astonishing arsenal of complex molecules to defend themselves or attack their rivals.
Over 60% of all antibiotics in clinical use today are derived from natural products, primarily from soil bacteria called actinomycetes .
The discovery of penicillin by Alexander Fleming in 1928 launched the modern era of antibiotics and demonstrated the medical potential of microbial compounds .
Scientists collect samples from diverse and often extreme environments—deep-sea sediments, volcanic hot springs, the roots of exotic plants. Why? Because harsh conditions force microbes to evolve unique survival strategies, which often involve producing novel chemicals. These microbes are then carefully separated and grown in pure cultures in the lab.
Once a promising microbe is found, researchers must figure out what compound it's producing. Using advanced techniques like Nuclear Magnetic Resonance (NMR) and Mass Spectrometry, they can determine the precise 3D structure of the molecule, atom by atom. It's like solving a microscopic jigsaw puzzle.
Instead of just harvesting the compound, scientists now want to know how the microbe makes it. By sequencing its DNA, they can identify the specific set of genes (called a gene cluster) that acts as the instruction manual for building the molecule .
Nature's molecules aren't always perfect for human medicine. They might not be absorbed well, or could have side effects. Using chemistry, scientists can tweak the original structure, creating semi-synthetic derivatives that are safer, more effective, or more stable.
In 2015, a team led by Dr. Kim Lewis at Northeastern University announced a groundbreaking discovery: a new antibiotic named Teixobactin, which was effective against drug-resistant bacteria like MRSA without them showing any signs of resistance.
For decades, 99% of soil microbes refused to grow in lab petri dishes, remaining an untapped "microbial dark matter." This meant that the vast majority of potential drug-producing microbes were inaccessible to researchers.
The team's breakthrough was the development of the iChip (isolation chip), a device that allows microbes to grow in their natural soil environment while being isolated in individual chambers.
A soil sample is highly diluted so that only a single microbial cell is placed into each small channel of the iChip.
The iChip is then submerged back into the original soil environment, allowing the microbes to grow in their natural habitat.
Once the microbes formed colonies, they were screened for antibiotic activity by exposing them to pathogens.
One particular bacterium, Eleftheria terrae, produced a compound that effectively killed Staphylococcus aureus.
Teixobactin targets lipids (building blocks of the bacterial cell wall) rather than proteins. Since lipids are not encoded by genes, bacteria find it incredibly difficult to develop resistance through mutation.
It was highly effective against a broad spectrum of Gram-positive pathogens, including strains resistant to all other known antibiotics .
Minimum Inhibitory Concentration (MIC) – the lower the number, the more potent the antibiotic.
| Bacterial Pathogen | Teixobactin MIC (µg/mL) | Vancomycin MIC (µg/mL) |
|---|---|---|
| Staphylococcus aureus (MRSA) | 0.25 | 1.0 |
| Mycobacterium tuberculosis | 0.125 | 1.0 |
| Enterococcus faecalis (VRE) | 0.5 | >128 |
| Bacillus anthracis | 0.125 | 0.25 |
Data adapted from Ling et al.
Comparison of microbial cultivation methods
| Class of Compound | Example Drug | Medical Use | Original Microbial Source |
|---|---|---|---|
| Beta-Lactam Antibiotic | Penicillin | Treats bacterial infections | Penicillium rubens (fungus) |
| Glycopeptide Antibiotic | Vancomycin | Last-line defense against MRSA | Amycolatopsis orientalis |
| Statin | Lovastatin | Lowers cholesterol | Aspergillus terreus (fungus) |
| Anticancer Agent | Bleomycin | Treats various cancers | Streptomyces verticillus |
| Immunosuppressant | Cyclosporine | Prevents organ rejection | Tolypocladium inflatum (fungus) |
What does it take to hunt for these molecular treasures? Here's a look at the essential toolkit used in natural product research.
A nutrient-rich jelly or liquid used to grow and maintain pure cultures of microbes in the lab.
A device with multiple small wells used to isolate and grow "unculturable" microbes in their natural environment.
Used to separate a complex mixture of compounds from a microbial extract into its individual parts.
A powerful machine that uses magnetic fields to determine the 3D structure of an unknown molecule.
Precisely measures the mass of a molecule, helping to identify its chemical formula and structure.
Tools to amplify and read the DNA of a microbe, allowing scientists to find gene clusters responsible for bioactive compounds .
The quest for bioactive natural products from microbes is far from over.
It's a journey that takes us from the soil in our own backyards to the most remote corners of the planet, all in search of nature's next miracle drug. With new tools like the iChip and advanced genetic engineering, we are no longer passive collectors but active participants, able to explore the vast uncultured microbial world and even engineer microbes to produce better medicines.
In the intricate chemical language of the smallest life forms, we continue to find solutions to some of our biggest human challenges. The next breakthrough antibiotic or anti-cancer drug might be waiting in a soil sample from your own backyard, produced by a microbe that has never been cultured before.