21st Century Antibiotics

Three decades ago, it was widely believed that antibiotics had conquered bacteria. But as antibiotic-resistant bacteria have proliferated, pharmaceutical companies have searched for a broad-spectrum drug that could kill them quickly and safely without falling prey to bacterial resistance (See 'Renewing the Fight Against Bacteria' and 'Retracing Steps to Find New Antibiotics'). Now, in the first supramolecular approach to antibiotic drug design, the answer may be near. Researchers at The Scripps Research Institute have created a synthetic peptide compound that invades disease bacteria and, once inside, forms stacks of tiny jewel-encrusted rings called cyclic peptide nanotubes. These nanotubes kill bacteria by punching holes in the membrane. Tests carried out in vitro and in vivo demonstrated successful killing of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE), among other bacterial pathogens, within minutes, the authors reported last year in Nature.1 "We saw that nanotubes gave us the opportunity to save many lives, and for a scientist, I think, that's the most gratifying thing that can happen," says lead investigator and chemist, M. Reza Ghadiri. Before this work, scientists recognized the antimicrobial efficacy of natural peptides, but had trouble converting that knowledge into functional therapeutics. "New antibiotic structures are all too rare," says Tomas Ganz, a professor of medicine at UCLA, in an accompanying commentary.2 But he describes the design and initial testing of these new cyclic peptide antibiotics as "an exciting advance in this quest." Peptide Structure Key to Function Ghadiri's nanotubes are small assemblies comprised of six- and eight-residue cyclic D,L-a-peptides. Built with alternating, right- and left-handed amino acids joined end-to-end, the peptides expose their amino acid side chains outside of the ring. (In nature, only the left-handed L-amino acids are found in peptides, but synthetic peptides can use both right- and left-handed forms.) When the peptides enter the charged environment of the bacterial membrane, they become sticky, forming antiparallel, hydrogen-bonded stacks, which kill bacteria by destabilizing the electric potential and ion gradients needed for survival. This peptide structure evolved in Ghadiri's lab over the past decade. In 1994, he discovered that peptides created with three consecutive hydrophilic amino acids and a stretch of alternating hydrophobic amino acids, L-tryptophan and D-leucine, would enter biological, lipid membranes and stack inside them. That was when he realized that the cyclic peptides might be used as antibiotics, and began focusing on how the technology could produce better drugs. Replacing the three amino acids in the hydrophilic area with different amino acids, Ghadiri changed the peptides' membrane permeability, allowing them to enter and form the bactericidal nanotubes. Over the years, Ghadiri learned to manipulate the peptides so that they target and invade specific bacterial cell membranes. "The peptide nanotubes can sense small differences between membranes, and know what is the right environment for them," he says. The key, Ghadiri says, is defining the amino acids sequences so that the peptides selectively strike bacterial membranes. Peptides have a large "sequence space" (compared to single molecules) that allows their functionalities to be manipulated without losing their activity. Instead of the specific lock-and-key design of single molecule antibiotics, which only works as long as the bacteria don't change in any way, these structures can act more like a universal key that molds itself into the targeted lock. Thus, small changes in bacteria won't deter the cyclic peptides from finding and fitting into their target. This flexibility could help nanotube-based drugs escape resistance and have a longer therapeutic life, Ghadiri notes. The hunt for antimicrobial agents was once limited to microbiologists and medicinal chemists, but today, organic chemists like Ghadiri have joined the search. Microbiologists who specialize in bacterial physiology express both excitement and caution about this trend. "I think it's a good thing that chemists have an interest in bacteria," says Abigail Salyers, bacterial physiologist at University of Illinois and president of the American Society of Microbiology. "But it would make sense for chemists to consult with bacteriologists in doing this work." Unless collaboration occurs between the fields, she says, basic mistakes might be made about bacteria's functioning and time will be wasted. Ghadiri's multidisciplinary lab currently includes chemists, biologists, and others, including scientists from two pharmaceutical companies. His research group is now testing the different ways that the peptide structures can be manipulated and used for antibiotic purposes. Ghadiri plans to partner with a pharmaceutical or biotechnology company and take the nanotubes into human trials within three years. "My hope is that within a decade, we'll have several useful drugs based on nanotubes on the market," he says. Jennifer Fisher Wilson (jfwilson@snip.net) is a contributing editor. References 1. S. Fernandez-Lopez et al., "Antibacterial agents based on the cyclic D,L-a-peptide architecture," Nature, 412:452-5, July 26, 2001. 2. T. Ganz, "Chemistry: Rings of destruction," Nature, 412:392-3, July 26, 2001.

21st Century Antibiotics

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