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Mar 18, 2014

DIY Molecular Drill Bits to Defeat Superbugs

  • Antimicrobial peptides (AMPs), naturally occurring and otherwise, are well-known for their ability to bore through the tough outer membranes of bacteria. In fact, AMPs have been called “molecular drill bits.” While about 1,000 unique AMPs have been identified from sources as varied as fly larvae, frog skin, and human immune system cells, designing new AMPs has proven to be challenging. For a newly designed AMP to serve as an antibiotic, it must demonstrate specificity; that is, it should disrupt bacterial but not mammalian outer membranes. Also, AMPs should not resemble naturally occurring AMPs too closely, in case pharmaceutical deployments of AMPs are found to promote bacterial resistance.

    Bacterial walls have been conserved though a long history of evolution, so researchers are optimistic that bacteria will have difficulty “learning” how to resist to AMPs. One such researcher is Georges Belfort, Ph.D., head of the Biomolecular Separations Research Group at Rensselaer Polytechnic Institute (RPI). “It’s going to be much more difficult for a bacterium that’s been around for millions of years to reconfigure its membrane,” Dr. Belfort notes. “That’s the core protective structure that has helped it survive this long.”

    Dr. Belfort and his team at RPI have demonstrated an abiding interest in AMP mechanisms, and they have been exploring AMPs as a way to deal with the alarming rise of resistance to existing antibiotics. “If the bacteria build resistance to all current treatments, you’re dead in the water,” remarks Dr. Belfort.

    In his review of recent work on AMPs, Dr. Belfort discovered a database filtering technique developed by another group, reported in 2012. He integrated this technique with his own innovations to create a kind of design-your-own-AMP model, which he described March 17 at the 247th National Meeting & Exposition of the American Chemical Society.

    Dr. Belfort’s presentation, entitled “Molecular drill bits as antibiotics,” explained that by “combining a new de novo design approach, database filtering, protein engineering, and rational design with several complementary measurement methods, we synthesize and test AMPs and derive structure-activity relationships for the most potent stable AMPs.”

    Dr. Belfort reports that his lab designed and synthesized three novel AMPs designed to drill into the thick walls of tuberculosis cells. When they tested them in the lab against Mycobacterium tuberculosis and a similar bacterium, M. smegmatis, all three AMPs killed the bacteria. One worked better than the others—but not as well as kanamycin, which is one of several antibiotics in the arsenal against tuberculosis that some strains have developed resistance against.

    The Belfort lab is now developing a laboratory test that will allow it to tell within hours rather than weeks if an AMP is working against M. tuberculosis. Also, it continues to focus on improving its designs and understanding exactly how AMPs work. The lab’s website contends that “potent, stable, amphipathic AMPs together with a fundamental understanding of their mechanism of cell disruption are urgently needed.”

    “Low stability, inadequate bacterial killing, high manufacturing cost, and unclear disruption mechanisms limit the enormous potential of AMPs as novel antibiotics for therapeutic applications,” the website continues. “We aspire not only to learn Nature’s rules for potency and stability of AMPs, but, with modern protein engineering and rational methods, we aim to improve and surpass the performance of native AMPs.”



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