Pedro R. L. was told by his doctor that his leukemia was in complete remission after six long rounds of treatment. He contracted Covid-19 while his body was healing. The man was admitted to the Madrid University Hospital. He developed severe pneumonia after initial treatment failed. A phase 3 clinical trial for treating hospitalized COVID patients was recommended by his doctor.

Few drugmakers would have predicted that the seafloor around Es Vedr, an uninhabited rocky island off the southwestern coast of Ibiza, Spain, would lead to the discovery of plitidepsin. The site is thought to have inspired Homer's tale in The Odyssey about sailors beinglured to their deaths by sirens. While diving on a reef full of purple corals and red sea fans, scientists pulled a pale-yellow tunicate, Aplidium albicans, that looked like a bunch of facial tissue.

tunicates draw water through their bodies to feed on plankton. They need strong chemical defenses to fight off infectious organisms and that makes them promising sources for medicines.

A compound from the A. albicans specimen was isolated by pharmaMar. Cancer drugs are more profitable than other drugs. After decades of research and testing, plitidepsin was approved for use in Australia.

The scientists at the company quickly proved that plitidepsin was superior to competing antivirals in head-to-head trials. The phase 1-2 clinical trial for hospitalized COVID patients ended in 2021. 74 percent of the patients with moderate disease recovered completely within a week of their first dose. By December, the phase 3 trial will be done. According to Jose Jimeno, plitidepsin appeared to be superior to other COVID antivirals. After two courses of treatment, Pedro R. L. was symptom free.

Freezer racks house 18,000 microbe strains collected over 30 years. Scientists grow the strains in cultures, test their biological prop­erties and may sequence their genomes look­ing for exploit­ able genes. Credit: Devin Oktar Yalkin

Most of the drugs that are approved today were isolated from animals. The tunicate, Ecteinascidia turbinata, yielded a mixture of genes that led to the drugs Yondelis and Zepzelca. Halaven is a drug used to treat late-stage breast cancer that was created by a black sponge. The venom from a cone snail led to Prialt.

Mollusks and coral have yielded promising compounds. According to Drew Harvell of Cornell University, the invertebrates have been living in this soup for 600 million years. It takes an average liter of water to contain one billionbacteria and 10 billionviruses. Over the past few decades, scientists have learned that the majority of the defensive substances in marine animals are produced byMicrobes. The Georgia Institute of Technology led a team that tested five species of sea slugs from the Red Sea and foundbacteria that were resistant to antibiotics.

Drug discovery scientists who used to focus on land-based biology now realize that the most likely source of marine-derived medicines is microbes. There are 23 new drugs currently in clinical trials, 16 of which are produced by microbes. Scientists have isolated thousands of promising compounds from marine microbes, which shows the variability of marine conditions. microbes have trouble maintaining a fluid balance on land The ocean is a welcoming environment.

It has taken decades for most approved marine drugs because of insufficient funding and because isolating, testing and producing large quantities of novel compounds is time consuming. Recent advances in chemistry and computation are allowing scientists to be more efficient in searching for life-saving medicines from the sea.

Gene Targets

In 1989 Paul Jensen brought some of the seafloor from the Bahamas back to his lab to be used for medical purposes. It was difficult. The first challenge he faced was to grow marinebacteria in lab conditions that are an approximation of the ocean. Even though they weren't subject to the same stimuli they would face in their natural environment, he had to convince them to make at least a few of the molecule in their arsenal.

Jensen was able to find a novel cancer-killing molecule in a new species ofbacteria. The deadly brain cancer that claimed the lives of John McCain and Beau Biden has been treated with a compound now marketed as marizomib. The FDA has yet to approve it. Jensen and others were motivated to look for better approaches after seeing how long it took for Marizomib to yield a new medicine.

Their work had changed by the early 2000s. The first full genome sequence for marine microbes, including S. tropica, showed that species that produced just a few compounds in lab cultures could usually make many more. In a few years, metagenomics revealed more hidden potential. Scientists began to find clusters of genes in species they had not cultured in the lab.

Jensen is interested in the molecule instead of the microbes that make them. Over the course of the past year, his team has waded into the seagrass beds off San Diego's Point Loma peninsula to submerge sheets of absorbent beads that pull organic molecule out of the sea water. Jensen is back in the lab analyzing samples for compounds that can act on living organisms.

Paul Jensen (left) has been investigating ocean com­ pounds for potential drugs for decades. A researcher from his lab (right) dips a sheet studded with absorbent resin beads that can pull organic molecules out of seawater. Credit: Devin Oktar Yalkin

He already has a hit, a compound with an unusual carbon skeleton that includes a group of enzymes-reactive molecules. Existing medicines might work differently than this novel structure. Jensen thinks it will kill cells. We hope to get a sense of its target.

He needs to match the compound to its producer. Enormous databases of marine microbes and compounds, along with the computing power needed to correlate them, are enabling scientists to link chemicals to genes efficiently. This approach is called pattern-based genome mining and it was pioneered by the University of Strathclyde's Katherine Duncan. Only recently has the technique become feasible. She says that they haven't been able to compare the data sets.

This technique is being used by Duncan to analyze the dark cores from the ocean floor. There are at least two new species of marinebacteria in the samples. On land, members of the same group live in close proximity to ants and produce anti-bacterial and antifungal compounds that help the ants fight off diseases. The marine cousins are capable of yielding anti-infective drugs.

Scientists such as Duncan and Jensen have to figure out which discoveries warrant the most attention. Nadine Ziemert is a microbiologist at the University of Tbingen in Germany. A modified copy of the toxin's cellular target can be used to protect itself from its own weapon.

Researchers can use the Antibiotic Resistant Target Seeker to find resistance genes related to specific cell functions by uploading their own genomes. As researchers speed their work to sequence the genomes of species from under explored environments, the database will become more valuable. The promise of Ziemert's target seeker has led to the creation of a similar tool by Hexagon Bio.

New Antibiotics

At the right time, targeted genome mining is a great idea. There is a need for more drugs to treat emerging infectious diseases. New drugs are desperately needed to treat diseases. Increasing resistance to antibiotics has made it difficult to treat many infections, including pneumonia, gonorrhea, blood poisoning and other diseases. Antibiotic resistance is one of the gravest threats facing humankind.

It seems clear that marine microbes have the potential to address the crisis because they are under studied. Richard Payne is excited about the fact that they can treat Tuberculosis. Over the last 10 years, Tuberculosis has been the greatest killer among infectious diseases, and with all the efforts that have gone to COVID, we've gone backwards with our control of the disease. There is a need for an antibiotic that targets a different disease.

There is a horseshoe of white sand on a small peninsula in South Korea known for its ideal windsurfing and kitesurfing conditions. The compound prevents M.tuberculosis from properly disposing of its waste. One of Payne's chemical analogs was so potent that it wiped out a lab-grown tuberculosis colony in three days. The drug works well in zebra fish and is being tested in mice.

Academics have been able to find and develop new antibiotics because the drugs sell so cheaply that pharmaceutical companies don't want to pursue them. Treatments for neglected tropical diseases like Malaria are the same. William Gerwick isolated a molecule from a tuft of cyanobacteria on a boat's mooring line. A frequent first line of research was the synthesis of a set of analogs.

A marine invertebrate recently cap­tured by a sub­mersible in the deep sea off southern Cali­fornia (2,500 meters down) remains frozen, waiting to be identified. Credit: Devin Oktar Yalkin

Gerwick focused on other projects after the results were not great. A colleague suggested that they test his analogs on Malaria parasites, and the result was striking. Gerwick says that one of them was very responsive against the disease. It wasn't harmful to humans.

Gerwick is trying to find a new anti-malarial drug. The discovery is a reminder of the possibilities in the thousands of marine compounds scientists have identified.

Carmaphycin B reminds us that technological advances alone won't deliver new drugs, and that a willingness to exploit it is often required. Joshawna Nunnery was supposed to be diving somewhere else on the day she collected thebacteria. When her lab mate and diving partner contracted the mosquito-borne disease, she had to change her plans and snorkel near the research station.

As investment in ocean exploration grows, there are more opportunities to take advantage of such happenstance. Anna Gauthier was one of the first scientists to sample deep-seabacteria from the islands on a recent expedition to the central Pacific Ocean. Gauthier, a PhD student at Harvard University, planned to conduct immune response experiments during the expedition so she didn't immediately freezebacteria she pulled from the sea. She startedculturing the organisms on the ship.

Salinispora bacteria from the sea, cultured in a lab dish, pro­duce a cancer­ killing molecule marketed as marizomib that has just com­pleted phase 3 trials as a drug for glioblas­toma, a deadly brain cancer. Credit: Devin Oktar Yalkin

The technique provided a benefit that was not intended. She grew a lot of different types ofbacteria that didn't cause an immune response from mammals. The finding has the potential to lead to a medical advancement.

Scientists such as Duncan in Glasgow are motivated by the promise of new medicines and public health crises. She knows people who have been on last-line antibiotics. My grandma passed away from sepsis. Everyone has a story.

Duncan hopes the stories will change over time. She thinks that the marine environment is undiscovered. There is a plitidepsin out there. Maybe it's already in a lab.