Mother Nature, the ultimate drug designer: why are we still using cheap synthetic compounds?

“I did not invent penicillin. Nature did that. I only discovered it by accident.”
– Alexander Fleming

Natural products – chemicals produced by organisms in nature – have been the basis of medicine for centuries. Aspirin is based on a chemical in willow tree bark. Morphine comes from the opium plant. Penicillin was discovered in a mold. Nature is the grand architect behind a major proportion of modern drugs. And yet, pharmaceuticals are focused on sub-par synthetic compounds.

Natural products are secondary metabolites: complex, diverse, highly specialized compounds produced by living things. Many evolved as defense mechanisms against other organisms. Certain microbes, for example, spew out potent anti-bacterial toxins that kill competing microbe species. Streptomycin, chloramphenicol, and tetracycline – three widely-used antibiotics – were all discovered in soil bacteria.

*Question Everything: This is not about “chemicals bad, nature good!” — nature is literally full of chemicals!

Another important thing to consider. When we say “natural products”, in this context, we’re not necessarily talking about rose hip oil, echinacea, or other plant extracts you might find in a naturopath’s medicine cabinet. We’re talking about specific chemicals — yes, chemicals! — that are evolved and produced in nature.

In some cases, these chemicals come from plant extracts like the ones I mentioned, many of which do have real medicinal properties. In others, they come from microbes, fungus, or even animals. Keep reading below!

The “Golden Age” of antibiotics

Fleming’s discovery of penicillin in 1929 launched the antibiotic “Golden Age”. In the years surrounding WWII, the pharmaceutical industry churned out dozens of new antibiotics in over 20 unique classes. A few were engineered synthetically, but most were discovered in microbes. Bacterial infections went down dramatically worldwide.

Sadly, it couldn’t last, and soon discovery came to a screeching halt. Since the 1960’s, only 2 new classes have been marketed. After years of blasting everything with the same antibiotics, organisms had evolved resistance mechanisms. Existing drugs stopped working; antibiotic-resistance infections began to run rampant. Having picked the “low-hanging fruit” of anti-bacterials, our arsenal was drying up. Bacteria were developing resistance faster than we could come up with new weapons. It was crucial that we find new drugs, with new targets, and fast.

The rise of high-throughput screening

Researchers turned to a rising technology called high-throughput screening (HTS), in which thousands – even millions – of compounds are screened against potential targets. Some top-of-the-line HTS robots can push through 100,000 compounds per day. The idea was that by screening millions of compounds, we were bound to find some with antibacterial activity.

To save costs, pharmaceutical companies put together compound libraries: huge databases of small molecules in just about every configuration they could think of. Despite the proven effectiveness of natural products, many companies decided they had low economic value, and instead turned to cheaper synthetic chemicals. These are screened against huge arrays of carefully selected pathogen targets in the search for “hits”.

Problem with synthetic compounds: quantity over quality

It turns out, we’re not as good at designing antibiotics as we’d hoped. Compared to natural products, synthetic compounds are simply not a high-quality source of drugs. Even now, after years of fine-tuning HTS, success rates for novel compounds are extremely low. Companies might spend years looking for drug candidates and still come up empty.

Time and money are precious resources in drug development; it takes 10-15 years and millions of dollars – even billions – to develop a single drug from “farm-to-table.” There are four major steps of drug development: 1) screen compound library and identify “hits”; 2) confirm hits as lead compounds; 3) advance through clinical trials; and finally, 4) successful release of drug.

From beginning to end, maybe 1 in 10 million compounds screened – and that’s if we’re being generous with our numbers – will become successful drugs for infectious diseases. This number has not significantly improved over the years.

The solution? Bring back the old school methods

I spoke to Dr. Alex O’Neill, whom I met while studying infectious diseases at the University of Leeds. Dr. O’Neill is an Associate Professor in the School of Molecular & Cellular Biology. He investigates how bacteria become resistant to antibiotics, and aims to understand how to get around this problem in our search for new drugs.

Research shows that aiming at multiple pathogen targets is crucial to avoid resistance. HTS often involves pinpointing single enzymes or viral proteins, then expanding to see whether the drug-target interaction holds true in the actual cell. This is incredibly inefficient, and Dr. O’Neill describes it as “an important limit of high-throughput screening”.

The most effective antibiotics are discovered by testing for anti-pathogen activity first, then teasing apart the molecular mechanism. “The most successful class of antibiotics are the beta-lactams, discovered in a whole-cell system,” says Dr. O’Neill. “Basically, the old school approach is the way to do it.” For antibiotics, this means turning our focus back to bacterial assays and away from gigantic small-molecule databases. Newer HTS systems do target whole-cell systems, but they still insist on using synthetic libraries.

Dr. O’Neill is a major proponent for the study of natural products produced by microbes, “the only true validated resource” for antibacterial compounds. “The real proof of the relative strength of natural product screening is the proportion of natural compounds in use,” he says. “There are only a handful of synthetic compounds.” In fact, natural products still account for half of newly-discovered drugs since the 1980’s, and approval rates for naturally derived products are climbing, even though very few are screened compared to synthetic compounds.

That doesn’t mean HTS has no place in drug development; “HTS is a tool, it’s not a problem,” says Dr. O’Neill. But a dish is only as good as its ingredients, and high throughput is useless without high quality compounds. Natural products are more biologically relevant than synthetic drugs. Unlike synthetics, they are ready-made to be active within cells. They contain fewer heavy metals and can be extremely stable. Importantly, because of their high complexity and diversity, they often have multiple targets, making them less susceptible to resistance.

So what’s the hold-up?

There are certainly barriers to natural product research. When it comes to plant-based chemicals, for example, high throughput can be a challenge. Natural products are difficult to patent. With HTS being all the rage, pharmaceutical companies see large compound libraries as more economically viable. “One of the reasons companies didn’t focus on natural product research was that it was always done on a really piecemeal level”, says Dr. O’Neill. “We just don’t have comparable compound libraries of natural products; it’s relatively straightforward to assemble synthetic compound libraries.”

However, with improved technology, HTS of natural products is becoming a reality, particularly when it comes to compounds produced by microbes. Mass production is a disappearing problem; not just for bacteria, which are easy to culture large-scale, but for plant-based chemicals as well. In 2006, for example, researchers at UC Berkeley found a way to engineer yeast to mass-produce the precursor for artemisinin, the antimalarial compound that comes from the herb Artemisia annua.

Potential gold mines for natural compounds

A very small portion – less than 15% – of terrestrial plants have been explored for natural product research. Strikingly, less than 1% of the microbial world has been tapped.

Almost two-thirds of natural products come from a group of bacteria called Actinomycetes, which include the Streptomycetes. Streptomyces griseus, for example, is responsible for streptomycin, the Nobel Prize-winning anti-tuberculosis drug. A single strain can produce over 30 different secondary metabolites. And it’s not just antibiotics; Actinomycetes produce antibacterial, antifungal, antiparasitic, immunosuppressant, and anti-viral compounds. S. roseus produces a protein that inhibits Marburg virus; other species produce compounds that inhibit polio and HIV. Dr. O’Neill calls Actinomycetes the “low-hanging fruit” for natural compounds, saying, “Their metabolic capabilities are much bigger than we originally thought.”

Potent anti-viral compounds have been found in fungi, plants, and even marine sponges. In my lab, I study certain plant-based extracts, traditionally used as anti-inflammatories in non-Western medicine, that actually have anti-viral properties. Feverfew, for example, can protect cells against viruses like Herpes simplex and Epstein-Barr by inhibiting inflammatory pathways. Milk thistle extract may protect liver cells from Hepatitis C. Artemisinin, mentioned earlier as an anti-TB drug, also has broad-spectrum activity against many different viruses.

Drugs could even come from our own gut; the human microbiome, which may produce compounds important to the host-pathogen relationship, is an up-and-coming source of natural product research. There are also a number of compounds that have already made it part-way through the pipeline, according to Dr. O’Neill; “There are thousands of known antibacterials not being put to clinical use,” he says. “They were identified in an era when there was a glut of compounds.” Re-opening the case on these compounds could give us a much-needed head start in our pursuit of new drugs.

Drug-resistant infections are becoming a worldwide epidemic. It is critical that drug developers push for high-quality source material in their search for new drugs. It’s time to use technology to revive and upgrade tried-and-true methods.

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