Ann: Successful Placement of Entitlement Offer Shortfall, page-5

No obvious thread to post this so its here. Thought it may be of interest to some on here.

Highlights 2 things for me.

Desperation of scientists to find new antibiotics
The levels to which people are extending the search


And RCE is sitting right here in plain sight !

Dow Jones25/05 00:00

By Dominique Mosbergen

Buried in the DNA of the long extinct woolly mammoth is a compound that scientists hope will one day yield a lifesaving antibiotic.

In experiments, mammuthusin, as the compound is called, has eradicated superbugs -- bacteria that are resistant to today's antibiotics and cause infections that are hard to treat -- says César de la Fuente, the bioengineer who helped discover the molecule.

De la Fuente, a professor at the University of Pennsylvania, is among a group of scientists probing ancient and unlikely places -- from genetic remnants of Neanderthals and extinct animals to unassuming backyard dirt -- to find new antibiotics. He says the search is desperate: "Antibiotic resistance is one of the greatest challenges we face as a society."

Infections caused by superbugs contribute to the deaths of more than five million people globally each year, and that toll is growing. Antibiotics are increasingly losing potency against even common infections. Without new drugs, antibiotic resistance could kill some 39 million people by 2050, a study last year predicted.

Now, fresh approaches to research are coming to an industry that has been slow to make new drugs and has been stymied by bacteria's ability to rapidly evolve defenses against those that exist. Most of the antibiotics we use today, and that have saved hundreds of millions of lives, were found in nature -- many of them decades ago and several by accident. Alexander Fleming discovered penicillin in 1928 after returning from vacation and finding that mold on a petri dish had prevented harmful bacteria from growing.

To help combat superbugs, doctors say we need new antibiotics with novel chemical structures or mechanisms of action. But only a handful of such drugs has entered the market over the past several decades.

De la Fuente is banking on artificial intelligence to help end this dry spell. He and his collaborators have built deep-learning algorithms to comb through enormous genetic databases to find peptides, or protein fragments, that have antibacterial properties. They have used this method to analyze animal venoms, the human microbiome and archaea, an underexplored group of microorganisms. They have also mined the genetic codes from fossils of long-extinct animals and humans, including Neanderthals and Denisovans. "This deep-learning model has opened a window into the past," de la Fuente says.

Most antibiotics used today are small-molecule drugs, mostly derived from bacteria and fungi. Small molecules can usually penetrate cell membranes with ease and are commonly administered as pills. Peptides, made up of short chains of amino acids, are larger and more complex. They tend to be more unstable in the body and can't easily be made into pills.

But advances have been made in recent years to improve the ability of peptide drugs -- which include some IV antibiotics, GLP-1s and insulin -- to be absorbed and used by the body. Antibacterial peptides are also plentiful in nature, as they are a part of the immune system in most organisms.

"Peptides are the next big thing in medicine," says de la Fuente, who launched a startup in January to further explore the antibiotic potential of mammuthusin and other peptides.

When the algorithms identify a new peptide with antibiotic potential, de la Fuente and his team use robots to manufacture the compound in their lab and then test it in mice infected with bacteria. So far, a few hundred peptides made in de la Fuente's lab have safely and effectively cured sick mice.

One of them was mammuthusin, identified in the genetic code of Mammuthus primigenius, a species of mammoth that last roamed the Earth about 4,000 years ago. The researchers discovered the peptide after mining a National Center for Biotechnology Information database of DNA sequencing data obtained from the fossils of extinct animals. In experiments, mammuthusin was as potent as polymyxin B, an antibiotic often used as a last resort for serious infections, according to a paper published in the journal Nature in June. The mammoth peptide effectively eradicated a type of bacterium that the World Health Organization has designated a critical pathogen because of its resistance to many common antibiotics.

The work with extinct species is "expanding the chemical space that we could explore," says James Collins, a bioengineer at the Massachusetts Institute of Technology. "These are molecules that evolved in a different time and a different setting."

Collins's lab has built its own algorithms to trawl chemical databases, such as those of existing pharmaceutical drugs, for potential antibacterial compounds. His lab is also experimenting with using generative AI to design completely new molecules that could kill bacteria. Collins and colleagues said in a 2024 paper that they had identified structurally unique antibiotics after analyzing more than 12 million chemical compounds.

Modern scientific techniques could uncover new opportunities in old hunting grounds, says Gerry Wright, a biochemist at McMaster University in Canada. "The way people found antibiotics in the past was they would go out and get something in the dirt," he says, referring to the fungi and bacteria that most antibiotics are derived from. Microbes have been waging war against one another for eons and have developed excellent defenses against one another. "There haven't been any compounds better than those made in nature," Wright says.

By the 1990s, however, scientists who were probing natural environments for antibiotics hit a wall: They kept finding the same antibiotic compounds again and again. "People got frustrated," Wright says. "It led to the misunderstanding that there was nothing more to find in these organisms."

But by using genetic sequencing and chromatography, a technique to separate mixtures, researchers in Wright's lab have been able to analyze known microbes and find less-obvious antibacterial molecules that were previously missed.

Patience has also proved fruitful. A researcher in Wright's lab took soil from a backyard in Ontario and extracted liquid from it that she kept in a petri dish under her bench for an entire year. Instead of adding nutrients to the dish and checking for organisms that grew quickly -- long typical for antibiotic-hunting -- she starved them and waited for rarer organisms to appear.

One of these slow-growing species was found to pump out a common antibiotic -- but more detailed analysis showed that it also produced a previously unknown antibacterial peptide. That peptide, which would be considered a structurally novel antibiotic, eradicated drug-resistant bacteria in mice, according to a March paper published in Nature.

"We are going back with different eyes and different techniques and discovering that there's still a lot of wealth to be found," Wright says.