Deadly Germs Are Catching Up With New Antibiotics
The germs have rallied--and they show no signs of retreating.
Deadly strains of bacteria have become resistant to even our most state-of-the-art drug defenses. Strains of tuberculosis, for instance, a disease once thought largely eradicated from the developed world, have become resistant to many drugs and, as a result, death rates are on the rise.
Even as new antibiotics are introduced, bacteria develops ways to thwart them. In at least one patient, the so-called superbug Staphylococcus aureus evolved resistance to one of the new antibiotics, a drug called linezolid that was released just one year ago. The patient, an 85-year-old man in a Boston hospital, died.
Authorities don’t foresee an end to the cycle. Even the most unusual new bacteria-killing compounds can be expected to eventually drive bacteria to resistance, scientists say. The latest, described in the July 26 issue of the journal Nature, takes aim at the bacterial cell membrane, as do many of the compounds discovered relatively recently in plants and animals. Scientists speculate that it will be more difficult for bacteria to evolve resistance to agents that target the membrane because, unlike conventional antibiotics, most don’t attack a specific molecule.
All such compounds are steps in the right direction, scientists say, and show promise at least in the short term in the endeavor to expand our drug arsenal in the eternal pathogenic arms race. “The question is how long will any one antibiotic hold its function before these pesky little beasts come up with an answer,” said Thomas Eisner, a chemical ecologist at Cornell University.
It’s a war that must be waged on many fronts, Eisner said. Vaccinations and improving health care and sanitation in the Third World are expected to limit the spread of disease. And new antibiotics must be a part of any strategy to check infections.
The need is greatest for antibiotics that work differently from the current generation. New antibiotics that act similarly to existing ones aren’t likely to be any more effective at countering resistance.
One promising source for novel weapons, called antimicrobials, against pathogens is plants and animals.
Looking to nature for antimicrobial inspiration is not a new idea: Most current antibiotics are modeled after natural compounds made by fungi and bacteria. But looking for antibiotics among organisms nearer to the human branch on the evolutionary tree has gained momentum only in the past 15 years, scientists say.
One of the first animal antimicrobials discovered was found in frogs. In 1986, Dr. Michael Zasloff, then a researcher at the National Institutes of Health, was doing research with African clawed frogs when he noticed that, though the frog tanks were filthy, the frogs’ incisions rarely became infected. The fruits of this rather grimy accidental discovery were simple chains of amino acids, the same molecules that make up proteins. Frogs ooze the amino acid chains, which Zasloff named magainins, through their skin to protect against infection.
Bacteria and fungi must make chemicals that kill their very similar competitors while leaving themselves unscathed. To do this, they often make chemicals that slip inside the intended bacterial cells and strike very specific targets, slowing or stopping those bacteria from making essential compounds necessary for survival and reproduction. A number of the chemicals used by fungi, bacteria and our current antibiotics attack sites on the cell’s protein factories called ribosomes.
Specific targets are relatively simple for bacteria to modify, and such modifications are one way bacteria resist antibiotics. Because animal and plant cells have less in common with bacteria, they can afford to use a cruder approach, essentially bludgeoning bacterial plasma membranes.
The plasma membrane serves as both fence and gatekeeper to bacterial cells. Small molecules such as water may pass easily through, but larger molecules like glucose or charged molecules can enter or exit only with the help of proteins that float like icebergs in the membrane.
If something breaks up the membrane, important molecules flow out and unwanted ones pour in, killing the cell. “It’s a much less fine attack on the bacterium,” said Thomas Ganz of UCLA Medical School. “So it is not quite as easy for the bacterium to resist.” Ganz researches microbe-killing peptides--strings of amino acids.
Some scientists cite the tiny tubes recently described in Nature as the most promising of the compounds inspired by membrane-targeting natural peptides.
These compounds, made by Reza Ghadiri and colleagues at the nonprofit Scripps Research Institute in La Jolla, are built up from tiny rings. The scientists made the rings by alternating natural “left-handed” or L-amino acids with their mirror image, synthetic “right-handed” or D-amino acids. Clusters of atoms, figurative thumbs of each amino acid, stick alternately up and down around the ring.
When certain specially designed rings come in contact with bacteria, they lodge in the bacterial plasma membranes. Once inside the fatty membrane, the thumbs attract each other, locking the rings together into a tiny tube, called a nanotube. Assembled tubes act like tunnels through the membrane, killing the cell by allowing vital compounds to leak out and others to flow in. The nanotubes’ most attractive features include their small size and adjustability. Tiny compounds are often better at penetrating tissue, said UCLA’s Ganz, though the unnatural amino acids might make the nanotubes too expensive to manufacture for antibiotics. The nanotubes’ adaptable architecture, however, may make the cost worthwhile.
Zasloff founded Magainin Pharmaceuticals to try to turn magainins into a drug, but so far the Food and Drug Administration hasn’t approved any magainin formulation for use even as a topical antibiotic.
Indeed, it is always difficult to turn a compound that works well in the lab into a drug on the shelf. No matter how well it works in a test tube, once in the body, the compound may react in ways no one predicted.
Peptides, such as defensins, could be more likely to spark an immune response than the chemicals that make up conventional antibiotics, said Stuart Levy, the director of the Center for Adaptation Genetics and Drug Resistance at Tufts University Medical School in Boston.
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Solana Pyne is a reporter for Newsday, a Tribune company.
