By David N. Leff

We¿re hearing a lot about patients¿ bill of rights, but not nearly enough about patients¿ bill of wrongs. Wrongful use of antibiotics is painting the human race into a corner of the ring, where infectious pathogens are winning the fight.

A few of these wrongs:

People suffering common-cold symptoms insist ¿ too often successfully ¿ that their physicians prescribe an antibiotic, even though these miracle drugs wield no magic wands against the viruses that cause common colds, coughs and flu. Antibiotics fed to farm animals to beef up their meat quickly enter the human food chain. It doesn¿t take an infectious bacterium all that long to evolve drug resistance against such overused dosing.

Recently, in three geographically separate patients, the deadly bacterium Staphylococcus aureus responded weakly to its once sure-fire antidote, the antibiotic vancomycin. What makes this worrisome is that worldwide, many strains of S. aureus ¿ a prime perpetrator of hospital-acquired infections ¿ is already resistant to all drugs except vancomycin. That makes it closer to becoming an unstoppable killer.

Today¿s issue of Nature, dated July 26, 2001, reports an entirely new concept in antibiotics, which rapidly rescued mice from death by S. aureus. The article¿s title: ¿Antibacterial agents based on the cyclic D,L-a-peptide architecture.¿ Its senior author is M. Reza Ghadiri, a chemist and molecular biologist at the Scripps Research Institute in La Jolla, Calif.

¿In this article,¿ Ghadiri told BioWorld Today, ¿we are describing an entire new class of antimicrobial agents. This is the first example of a nanochemical approach to drug design. The molecules assemble on their own, organize on their own and self-sort in the bacterial target membrane to form a hole-punching structure that kills.¿

Secrets Of Self-Assembling Nanotubes

¿What makes them self-assemble,¿ he explained, ¿is that we have designed these cyclic peptides based on alternating D (right-handed) and L (left-handed) chiral amino acids. These cyclic peptides adopt a flat ring-shaped structure, putting the amino-acid backbone at right angles to the side chains. The central pore in the nanotubes is about 5.0 to 7.5 Angstroms. They stack to form similar tubular structures with the amino acid side chains on the outside of the cylinders.

¿These side chains,¿ Ghadiri went on, ¿can sense and respond to the local environment. They interact with other molecules in the bacterial membrane. That¿s how the target recognition takes place, and how we can get selectivity out of these types of interaction, so that they assemble in the bacterial membrane, and not in mammalian cells.

¿We are all mammals ourselves,¿ Ghadiri observed, ¿eukaryotes, and we are trying to destroy bacteria, which are prokaryotes, without hitting the mammalian host ¿ the patient. When you make a drug, you don¿t want it to be toxic, so you have to select between different cell types, which ones you want to destroy.

¿The discs assemble to form tubes that penetrate the membrane,¿ Ghadiri recounted, ¿and that makes them leaky. Out pour the bacterial cells¿ contents ¿ the stored ions and electrical gradients that run their machinery. Once you collapse that gradient, and cross their biological membrane, they cease to function.¿

After preliminary toxicology tests of their four most advanced nanotube peptides, the co-authors conducted experiments to determine the antibiotic efficacy of one candidate protodrug. They infected three groups of six mice each with lethal doses of Staphylococcus aureus, resistant to a penicillin-like antibiotic. Forty-five minutes later they injected the animals intraperitoneally or subcutaneously with a bolus of the peptide. All mice in the no-peptide control group were dead within 48 hours. But 100 percent of the peptide cohorts survived, completely protected from the bacterium.¿

Many conventional antibiotics perform brilliantly until laid low by bacterial drug resistance. Ghadiri suggested that his nanotube peptide antibacterial agents may have better insurance policies.

¿No matter what you throw at the bacteria,¿ he pointed out, ¿eventually they become resistant to it. That¿s the fact, because evolution is a very powerful force. The fact that nature has not seen our synthetic peptides before,¿ he added, ¿is an advantage at the beginning. These compounds are very fast acting. They kill bacteria very quickly, unlike most known antibiotics on the market, which are bacteriostatic, rather than bactericidal. In our Staph aureus test, it took less than five minutes to kill. Conventional antibiotics would require several hours to days to complete their job.¿

In Drug Resistance, Nature Bats Last

¿So that¿s a positive thing,¿ Ghadiri observed. ¿What¿s more, the targets of these peptides are bacterial membranes. That means the pathogen has to do many things to change its membrane composition, and make it resistant. And that is more difficult to do. But rest assured the bugs will find a way to become resistant to these peptides.

¿However,¿ he continued, ¿the outlook for us is that we can also change the coats of our peptide nanotubes. And if any resistance develops against a given sequence, we will have another one that is reactive on that target. So our hope is that for some appreciable time, this new class of antimicrobial agents can ward off newly resistant pathogens.¿

Scripps has filed to patent the co-authors¿ novel nanotube antibacterials, but Ghadiri made the point, ¿We ourselves are not going into human clinical trials. We are doing basic research, which shows that this class of compounds is very promising. Now biotech and pharmaceutical companies should get involved in starting to develop actual drugs out of it ¿ which will take five to 10 years.¿ He is in very preliminary discussions with such companies that might be interested in taking on this work.

¿Possible side effects,¿ Ghadiri said, ¿will be considered when one needs to make actual antibiotics. That¿s when long-term effects have to be determined. There¿s a lot of work ahead of us to make an actual drug. Right now, we are trying to select new sequences against the great variety of bacterial pathogens, and moving toward describing sequences active against fungal diseases. We are also going to see,¿ he concluded, ¿if this class of compounds can be used against certain types of cancers cells.¿

No Comments