How it works - Brilacidin history
DeGrado, with the help of a powerful supercomputer simulation, has created new antibiotics that mimic natural ones but are far simpler to produce and more stable. They capture the essence of animal antibiotics in molecules that are one quarter the size and can be made with standard chemistry techniques. The supercomputer work "was absolutely critical" in crafting the antibiotic, says DeGrado. "It narrowed the choices tremendously [and converted it] from an intractable problem to a feasible one."
The first antibiotic from this work is now in human trials at the biotech firm PolyMedix, which DeGrado cofounded in 2002. In animal tests PolyMedix's drug PMX-30063 is at least as powerful as the gold standard hospital antibiotic vancomycin at killing key strains. The initial effectiveness trial in staph skin infections could yield results this year.
"It has been difficult, [the previous peptide drugs] have been of questionable efficacy and of course had toxicity. But this one looks like it will be quite effective and not very toxic," says Duke University infectious disease specialist Ralph Corey, who is a paid advisor to PolyMedix. "I hope it works."
New antibiotics are badly needed as bacteria become resistant to existing drugs. Because existing antibiotics target specific bacterial molecules, a mutation in the bacterium can render the drugs ineffective. One nasty bug inhabiting American hospitals, methicillin-resistant Staphylococcus aureus, is linked to 18,650 deaths each year, a 2007 study concluded. Pfizer's Zyvox is one of the only new classes to combat such killers strains. In contrast, the peptide antibiotics are less vulnerable to resistance because they infiltrate and damage the membrane that holds the bacterium together.
In 2000 DeGrado became curious about what was the simplest possible molecule that could mimic this membrane-infiltrating ability. He realized that the key was a two-sided structure. One side is attracted to negatively charged molecules on the surface of bacterial membranes. This, among other things, helps it to distinguish bacteria from human membranes, which have a less negative charge. The other side of the antibiotic contains an oily surface that is attracted to the greasy interior portion of the membrane.
Doodling on a scrap of paper with postdoctoral student Gregory Tew (now a professor at the University of Massachusetts), DeGrado came up with a crescent-shaped molecule that was somewhat similar to the polymer Kevlar used in bulletproof vests. He wasn't sure it would work, so he took it across the campus to molecular modeling expert Michael Klein. Klein took one look and was convinced that DeGrado was on to something. "I was so excited that I got [DeGrado] to sign and date the paper and gave it to my secretary" for safekeeping, recalls Klein, now at Temple University.
DeGrado, with the help of a powerful supercomputer simulation, has created new antibiotics that mimic natural ones but are far simpler to produce and more stable. They capture the essence of animal antibiotics in molecules that are one quarter the size and can be made with standard chemistry techniques. The supercomputer work "was absolutely critical" in crafting the antibiotic, says DeGrado. "It narrowed the choices tremendously [and converted it] from an intractable problem to a feasible one."
The first antibiotic from this work is now in human trials at the biotech firm PolyMedix, which DeGrado cofounded in 2002. In animal tests PolyMedix's drug PMX-30063 is at least as powerful as the gold standard hospital antibiotic vancomycin at killing key strains. The initial effectiveness trial in staph skin infections could yield results this year.
"It has been difficult, [the previous peptide drugs] have been of questionable efficacy and of course had toxicity. But this one looks like it will be quite effective and not very toxic," says Duke University infectious disease specialist Ralph Corey, who is a paid advisor to PolyMedix. "I hope it works."
New antibiotics are badly needed as bacteria become resistant to existing drugs. Because existing antibiotics target specific bacterial molecules, a mutation in the bacterium can render the drugs ineffective. One nasty bug inhabiting American hospitals, methicillin-resistant Staphylococcus aureus, is linked to 18,650 deaths each year, a 2007 study concluded. Pfizer's Zyvox is one of the only new classes to combat such killers strains. In contrast, the peptide antibiotics are less vulnerable to resistance because they infiltrate and damage the membrane that holds the bacterium together.
In 2000 DeGrado became curious about what was the simplest possible molecule that could mimic this membrane-infiltrating ability. He realized that the key was a two-sided structure. One side is attracted to negatively charged molecules on the surface of bacterial membranes. This, among other things, helps it to distinguish bacteria from human membranes, which have a less negative charge. The other side of the antibiotic contains an oily surface that is attracted to the greasy interior portion of the membrane.
Doodling on a scrap of paper with postdoctoral student Gregory Tew (now a professor at the University of Massachusetts), DeGrado came up with a crescent-shaped molecule that was somewhat similar to the polymer Kevlar used in bulletproof vests. He wasn't sure it would work, so he took it across the campus to molecular modeling expert Michael Klein. Klein took one look and was convinced that DeGrado was on to something. "I was so excited that I got [DeGrado] to sign and date the paper and gave it to my secretary" for safekeeping, recalls Klein, now at Temple University.
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Ronald A Phillips
