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posted by martyb on Sunday June 07 2020, @01:18PM   Printer-friendly
from the good-news-for-a-change dept.

'Poisoned arrow' defeats antibiotic-resistant bacteria: A dual-mechanism antibiotic kills Gram-negative bacteria and avoids drug resistance (SD)

Poison is lethal all on its own — as are arrows — but their combination is greater than the sum of their parts. A weapon that simultaneously attacks from within and without can take down even the strongest opponents, from E. coli to MRSA (methicillin resistant Staphylococcus aureus).

A team of Princeton researchers reported today [DOI: 10.1016/j.cell.2020.05.005] [DX] in the journal Cell that they have found a compound, SCH-79797, that can simultaneously puncture bacterial walls and destroy folate within their cells — while being immune to antibiotic resistance.

[...] "This is the first antibiotic that can target Gram-positives and Gram-negatives without resistance," said Zemer Gitai, Princeton's Edwin Grant Conklin Professor of Biology and the senior author on the paper. "From a 'Why it's useful' perspective, that's the crux. But what we're most excited about as scientists is something we've discovered about how this antibiotic works — attacking via two different mechanisms within one molecule — that we are hoping is generalizable, leading to better antibiotics — and new types of antibiotics — in the future."

[...] To prove its resistance to resistance, Martin tried endless different assays and methods, none of which revealed a particle of resistance to the SCH compound. Finally, he tried brute force: for 25 days, he "serially passaged" it, meaning that he exposed bacteria to the drug over and over and over again. Since bacteria take about 20 minutes per generation, the germs had millions of chances to evolve resistance — but they didn't. To check their methods, the team also serially passaged other antibiotics (novobiocin, trimethoprim, nisin and gentamicin) and quickly bred resistance to them.

Proving a negative is technically impossible, so the researchers use phrases like "undetectably-low resistance frequencies" and "no detectable resistance," but the upshot is that SCH-79797 is irresistible — hence the name they gave to its derivative compounds, Irresistin.

Journal Reference:
James K. Martin, Joseph P. Sheehan, Benjamin P. Bratton, et al. A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance. Cell, 2020; DOI: 10.1016/j.cell.2020.05.005


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  • (Score: 3, Informative) by The Mighty Buzzard on Sunday June 07 2020, @02:02PM (4 children)

    Plenty of antibiotics already do that. You get them back quickly enough after you've finished the course though. Faster if you don't go nuts with sanitizing everything.

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  • (Score: 1, Insightful) by Anonymous Coward on Sunday June 07 2020, @04:53PM

    by Anonymous Coward on Sunday June 07 2020, @04:53PM (#1004550)

    Absolutely, and it's ridiculous that we still have doctors prescribing antibiotics without knowing what strain of bacteria that they're targeting or taking precautions to protect/replace the innocent bystanders that get killed in the process.

    Bacteria are a huge part of our immune system as well as performing other helpful roles in and around the body. The medical community should show them far more respect as you're not realistically going to keep something completely free of bacteria.

  • (Score: 5, Interesting) by Azuma Hazuki on Sunday June 07 2020, @09:35PM (1 child)

    by Azuma Hazuki (5086) on Sunday June 07 2020, @09:35PM (#1004616) Journal

    It's not that easy. C. diff colonization and the resulting pseudomembranous colitis and dangerous diarrhea is a huge problem, and you don't get your gut flora back with just a couple of weeks of Chobani and oatmeal, or even probiotic supplements.

    Not to mention, fluoroquinolones like ciprofloxacin (and anything with *flox* in it generally) have a bizarre laundry list of seemingly unrelated side effects--QTc prolongation and tendon rupture, for example--that make me wonder if there's collateral damage being done to mitochondria. Macrolides like azithromycin, which ostensibly work by binding to the 50S ribosomal subunit of bacteria, also have weird side effect profiles, as do their aminoglycoside cousins which bind to the 30S subunit.

    And folate blockages remind me of drugs like methotrexate, usually used to treat cancer and rheumatoid arthritis. Just how selective are these new drugs regarding where they interfere with folate usage? If they're systemic and relatively indiscriminate, they border on chemotherapy with all that that implies.

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    • (Score: 2) by takyon on Sunday June 07 2020, @09:47PM

      by takyon (881) <reversethis-{gro ... s} {ta} {noykat}> on Sunday June 07 2020, @09:47PM (#1004623) Journal

      They say it doesn't affect human cells... much:

      It’s the holy grail of antibiotics research: an antibiotic that is effective against diseases and immune to resistance while being safe in humans (unlike rubbing alcohol or bleach, which are irresistibly fatal to human cells and bacterial cells alike).

      [...] There was one problem: The original SCH-79797 killed human cells and bacterial cells at roughly similar levels, meaning that as a medicine, it ran the risk of killing the patient before it killed the infection. The derivative Irresistin-16 fixed that. It is nearly 1,000 times more potent against bacteria than human cells, making it a promising antibiotic. As a final confirmation, the researchers demonstrated that they could use Irresistin-16 to cure mice infected with N. gonorrhoeae.

      [...] In particular, each of the two mechanisms — the arrow and the poison — target processes that are present in both bacteria and in mammalian cells. Folate is vital to mammals (which is why pregnant women are told to take folic acid), and of course both bacteria and mammalian cells have membranes. “This gives us a lot of hope, because there’s a whole class of targets that people have largely neglected because they thought, ‘Oh, I can’t target that, because then I would just kill the human as well,’” Gitai said.

      “A study like this says that we can go back and revisit what we thought were the limitations on our development of new antibiotics,” Huang said. “From a societal point of view, it’s fantastic to have new hope for the future.”

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  • (Score: 2) by driverless on Monday June 08 2020, @06:36AM

    by driverless (4770) on Monday June 08 2020, @06:36AM (#1004744)

    That was my reaction to the article as well, it's easy enough to find some compound that kills everything it touches, but how well does it do at not killing everything but its target? That'll be the real acid test of the current silver bullet.