Hidden Antibiotic Discovered In Soil Bacterium Kills Drug-Resistant Superbugs

Soil Bacterium Studied Since 1950 Just Yielded an Antibiotic That Outsmarts Superbugs

For decades, scientists assumed they had already identified every useful antibiotic out of the most well-studied soil bacteria. A new discovery suggests that assumption was premature.

Researchers have found a brand-new antibiotic hiding in plain sight, produced by a strain of bacteria that scientists have studied since 1950. The bacteria, Streptomyces rimosus, has long been known as the source of oxytetracycline, a common antibiotic used in both human medicine and agriculture.

Buried beneath that familiar drug was something entirely different: a compound called manikomycin, named from the Hindi and Punjabi word for “precious gem.” The name fits. Manikomycin kills drug-resistant bacteria by hitting a spot on the ribosome, the cell’s protein-building machine, that no known antibacterial drug had previously reached, according to the researchers.

That distinction matters enormously. The global antibiotic resistance crisis, in which bacteria evolve to shrug off the drugs designed to kill them, is partly a consequence of decades of recycling the same old drug blueprints. Manikomycin doesn’t follow any of those blueprints, which means the resistance defenses bacteria have built up against existing drugs don’t apply.

Overlooked for 75 Years in Already-Studied Bacteria

To find manikomycin, researchers didn’t travel to some remote corner of the world in search of undiscovered organisms. Instead, they went back to bacteria they already had, a library of 255 soil bacteria assembled specifically to maximize chemical novelty. The key wasn’t where they looked, but how.

Crude bacterial extracts are a bit like fruit punch. Everything gets blended together, and the minor flavors disappear into the dominant ones. Oxytetracycline is a potent, dominant antibiotic that had long been drowning out manikomycin’s signal. By using improved separation techniques that break those extracts into distinct components based on their chemical properties, the team isolated fractions that didn’t match any known compound in major scientific databases. Two of those mystery fractions turned out to contain manikomycin and related compounds, a previously unknown family of antibiotics the researchers called MKMs.

Manikomycin Disarms Drug-Resistant Superbugs at the Ribosome

Every living cell, including a bacterial one, needs to manufacture proteins to survive. That process runs on a cellular machine called the ribosome, which reads genetic instructions and assembles proteins piece by piece. Most existing antibiotics that target the ribosome do so by jamming well-known spots on that machine. Manikomycin does something different.

It targets what researchers call the E-site, an exit door on the large part of the ribosome where spent components are released after each step of protein assembly. Manikomycin wedges into that exit zone and blocks the tail end of a spent molecular carrier from settling into place, freezing the ribosome during a key movement step. Without protein production, vulnerable bacteria stop growing and, under the right conditions, can die. Using a high-resolution imaging technique called cryo-EM, researchers confirmed exactly where manikomycin sits on the ribosome at near-atomic resolution.

Crucially, that exit door looks different in bacterial ribosomes compared to mammalian ones. A protein present in human cells physically blocks the spot where manikomycin binds in bacteria. That structural difference likely explains why manikomycin was about 15 times weaker at blocking protein production in a mammalian cell-free test than in a bacterial one, with no detectable toxicity in the human cell lines tested.

Tested Against Real Drug-Resistant Strains of E. coli and Klebsiella

Published in Nature, the study found manikomycin showed activity against E. coli and Klebsiella pneumoniae, including multidrug-resistant clinical strains tested in the study. Existing resistance mechanisms found in clinical isolates did not protect bacteria from it.

In a test using human blood infected with a drug-resistant strain of K. pneumoniae, manikomycin reduced bacterial numbers by approximately 1,000-fold after six hours at five times the minimum dose needed to inhibit growth. Researchers also tested the drug in a tiny worm, a common stand-in for more complex infection biology. Worms infected with both a standard and a multidrug-resistant clinical strain of K. pneumoniae were treated with manikomycin, and 55 to 60 percent survived to day six, compared with 10 to 30 percent in the untreated groups.

Early tests in mice, however, revealed a real hurdle: the drug was cleared from the body too quickly, mostly eliminated within about 36 minutes after a single dose. No benefit was seen in the mouse infection model, pointing to a problem with how the drug moves through the body rather than whether it works. The researchers note that modifying the drug’s chemistry could address this, and work on analogues is underway.

What This New Antibiotic Discovery Means for Resistance

Manikomycin is not a medicine yet and still needs extensive development before any human testing could be considered. Researchers also identified how bacteria can develop resistance to it, primarily through mutations in the proteins that carry the drug into the cell, and the producing bacterium’s own self-protection mechanism gives scientists a roadmap for designing versions that sidestep that route.

Perhaps the most consequential takeaway has nothing to do with manikomycin itself. This discovery shows that some of the most well-studied organisms are still producing compounds that break entirely new ground.

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Disclaimer: This article is based on research findings and is intended for informational purposes only. Manikomycin is not an approved medication and has not been tested in humans. Readers should not interpret this article as medical advice.

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