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Powerful Antibiotics Found in Dirt

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Dirt

Caption: Researchers found a new class of antibiotics in a collection of about 2,000 soil samples.
Credit: Sean Brady, The Rockefeller University, New York City

Many of us think of soil as lifeless dirt. But, in fact, soil is teeming with a rich array of life: microbial life. And some of those tiny, dirt-dwelling microorganisms—bacteria that produce antibiotic compounds that are highly toxic to other bacteria—may provide us with valuable leads for developing the new drugs we so urgently need to fight antibiotic-resistant infections.

Recently, NIH-funded researchers discovered a new class of antibiotics, called malacidins, by analyzing the DNA of the bacteria living in more than 2,000 soil samples, including many sent by citizen scientists living all across the United States [1]. While more work is needed before malacidins can be tried in humans, the compounds successfully killed several types of multidrug-resistant bacteria in laboratory tests. Most impressive was the ability of malacadins to wipe out methicillin-resistant Staphylococcus aureus (MRSA) skin infections in rats. Often referred to as a “super bug,” MRSA threatens the lives of tens of thousands of Americans each year [2].

It might seem strange that soil would be the place to look for the most promising new antibiotics. But bacterial species in soil have been locked in a continuous antibiotic arms race with one another for millennia. When it comes to the chemistry needed to produce highly effective antibiotics, they are the experts.

In fact, molecules derived from bacteria have been the major source for antibiotics that doctors now prescribe to help with certain infections. But scientists had all but given up on discovering any new antibiotic compounds from bacteria cultured in the lab. It seemed that source had been completely mined, and new searches were mostly coming up empty.

Time for a new approach! In the study reported in Nature Microbiology, researchers led by Sean Brady at The Rockefeller University, New York took a different approach. They scoured DNA extracted from trillions of soil-dwelling bacteria, most of them collected by citizen scientists living all around the country and mailed to Brady and colleagues in plastic baggies.

While scouring through all that DNA, the researchers looked for something quite specific: novel clusters of genes that structurally look like those already known to be involved with calcium-dependent antibiotics. These are antibiotics that attack bacteria only in places where they have calcium present to help them communicate, move, differentiate, and carry out other basic cellular functions.

Brady and team didn’t have a lot of leads, as only a few calcium-dependent antibiotics are now known. What’s more, each of these known antibiotics fight bacteria in a slightly different calcium-dependent way.

But the researchers soon hit pay dirt (sorry, you knew that pun was coming). About 75 percent of their soil samples contained bacteria carrying the kinds of genes the researchers were looking for, suggesting that there are many promising calcium-dependent antibiotics yet to be found.

They focused on a particular new family of antibiotics, which turned up in almost 20 percent of the sequenced bacterial samples. They called the new family malacidins (Latin for, “killing the bad”). To recover all the genes needed to produce malacidins, the researchers went back to a sample of sandy, desert soil that they knew to contain many malacidin-producing bacteria.

First, they isolated and cloned the DNA. Then they inserted the cloned DNA into the genome of Streptomyces albus, a bacterium that is especially good at producing molecules in the lab. Those laboratory microbes began churning out two similar malacidin molecules. Interestingly, those malacidins didn’t look quite like what the researchers had expected to find. But, as expected, antibiotic activity of these compounds did depend on calcium.

The researchers found that the antibiotic compounds killed many multidrug-resistant pathogens, including several different strains of Staph aureus. They were also successful in treating a Staph-infected skin wound on rats, without causing any apparent toxicity or damage to the animals’ own cells.

Malacidins attack an essential part of the bacterial cell wall in a unique way compared to other existing calcium-dependent antibiotics. This mechanism is not only unique, but it is apparently difficult for other bacteria to circumvent. The researchers found that after 20 days of exposure to sublethal levels of malicidins, none of the tested lab bacteria showed any signs of becoming resistant to it.

Brady says that the next step is to tinker with the structure of the malicidins to see if they can come up with an even more effective version of the molecule. They’re also continuing to explore other related compounds found in nature.

As promising as malacidins are, they are just the start. Brady is convinced the bacterial world contains a largely untapped reservoir of antibiotics that have yet to be discovered. With the sophisticated genomic, analytical, and other tools now available, many of them will soon be found. It looks as though some of the solutions to the growing problem of antibiotic resistance have been hiding, quite literally, right in our own backyards.

References:

[1] Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogen. Hover BM, Kim SH, Katz M, Charlop-Powers Z, Owen JG, Ternei MA, Maniko J, Estrela AB, Molina H, Park S, Perlin DS, Brady SF. Nature Microbiol. 2018 Feb 12. [Epub ahead of print]

[2] Methicillin-Resistant Staphylococcus aureus (MRSA). National Institute of Allergy and Infectious Diseases.

Links:

Antimicrobial (Drug) Resistance (National Institute of Allergy and Infectious Diseases/NIH)

Sean F. Brady (The Rockefeller University, New York)

Drugs from Dirt (The Rockefeller University)

NIH Support: National Institute of Allergy and Infectious Diseases

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