Resisting antibiotics

Antibiotic resistance









 In the long run, misuse of antibiotics could be deadly.













































  rug resistance is an inevitable result of widespread antibiotic use.








  Got cipro?
White oval pills stamped 'Cipro' and '750'The anthrax scare has put an obscure antibiotic, ciprofloxacin, on the front pages. Earlier this week, Manhattan hospital workers became the latest to line up for cipro, as the drug is known on the street.

Anthrax is dangerous, but blanket dosing with antibiotics carries its own risks. We're not talking about side effects, but about the inevitable evolution of bacterial resistance.

Once upon a time, doctors expected antibiotics to extinguish infectious disease, and drug companies essentially quit looking for new antibiotics. The evolution of both bacterium and the AIDS virus, HIV, changed scientists thinking about that. HIV mutates fast enough to evade antiviral drugs.

While HIV is a virus (and not subject to antibiotics), a similar problem exists in the bacterial realm, where antibiotics have served as magic bullets against a host of bacterial diseases, like diphtheria, plague and tuberculosis.

Eventually, bacteria evolve resistance to antibiotics and eventually has arrived. Many nasty bacteria, including members of the Staphylococcus, Enterococcus and Mycobacterium (tuberculosis) families resist multiple drugs.

A natural problem
Resistance is not an accident, but a fact of evolution and chemistry, a logical outcome of the incessant, invisible struggle for existence among microorganisms.

Timetable showing 'years to resistance' for various drugs. Time to resistance is as short as five years.
Bacteria can become resistance to antibiotics in short order.

The creativity of bacteria in adapting to weird environments rests on their rapid multiplication, genetic exchange and frequent genetic errors. Errors, the building blocks for evolution, are "evaluated" by natural selection as an organism faces the demands of survival, and some are so beneficial that they are found in subsequent generations.

These factors explain why bacteria evolve much faster than, say, boa constrictors or duck-billed platypuses. This rapid evolution has produced antibiotic-resistant bacteria that can:

degrade or destroy the antibiotic with enzymes
change target molecules so the drug has nothing to attack
eliminate entry ports on the cell wall/or
pump the antibiotic from the cell

Mechanisms of resistance
Bacteria have two mechanisms for gaining these resistance tricks -- mutation and gene-sharing. A "point mutation" is a change in one base in the DNA molecule. From the bacterium's standpoint, a point mutation is a roll of the dice -- most mutations are harmful; only rarely do these changes give a bug a leg up on the competition.

But with bezillions of bacteria dividing and mutating every second of every day, inevitably some mutations will undermine any antibiotics present. As Charles Darwin might have realized -- resistance is only a matter of time and natural selection.

Translated: Brew a bunch of bacteria in a broth of nutrients, and many will prosper. But once you sprinkle some antibiotic into the cauldron, every bacterium will die -- except any that happen to resist the drug. From that point, through simple heredity, all their offspring are resistant.

Just like that!

Big, fat, white rooster looks off to his rightThat simple process is exactly what happens when farm animals are fed low-dose antibiotics to promote growth. A new study found Salmonella bacteria in 20 percent of ground turkey, beef, chicken and pork. Alarmingly, 84 percent of the bugs resisted at least one antibiotic, and 53 percent resisted three or more. The finding sparked renewed calls to control the dosing of farm animals with antibiotics, especially those used by people (see "Isolation of Antibiotic..." in the bibliography below) and our coverage of antibiotics in meat.

Natural resistance
Point mutations probably explain the quick evolution of resistance to cipro, the synthetic antibiotic that is the first line of defense against anthrax.

Cipro inhibits DNA gyrase, an enzyme that twists the double-helix of DNA for compact storage when it's not being duplicated during cell division. Without DNA gyrase, bacteria die -- that's why cipro kills so many types of bacteria. But a point mutation can eliminate cipro's target on the gyrase without inactivating the enzyme.

Because other mechanisms, such as changes in cell wall porosity, can also cause resistance to cipro, total resistance can depend on the total number of defenses.

It makes sense when you think about it, but resistance genes may originate in the same organisms (typically those living in the soil) that made the antibiotic in the first place. Since self-poisoning is an evolutionary dead-end, bugs need protection against their own offense if they make an antibiotic and have the antibiotic's target molecule. Logically, a gene for antibiotic resistance must evolve along with the gene for the antibiotic itself.

Heavy trafficking
While resistance can arise from point mutations, scientists have in recent years found a far more efficient route -- the bacterial swap-meet. While we wouldn't think of sharing our genes with, say, a naked mole rat or China-White hog, bacteria turn out to be surprisingly generous about donating genes -- even to different species. These travelling genes can carry resistance to multiple antibiotics.

The deadly mechanisms for moving genes include movement of DNA on:

viruses that extract DNA from one bacterium and insert it into others
fragments of chromosomes released by dead bacteria that are taken up by others
ring-shaped structures called plasmids

Plasmids: Rings of DNA move from one bacterium to another; free DNA: a bacterium breaks apart, releasing DNA that is taken up by the recipient; viruses: a virus moves DNA between bacteria.

Bacteria transfer resistance to antibiotics through three separate mechanism: plasmids, free DNA, and viruses.

The deadly source
The bacterial trafficking in genes is so common that antibiotic expert Stuart Levy writes that "the entire bacterial world can be thought of as one huge multicellular organism in which the cells interchange their genes with ease."

But why would bacteria give away genes in the first place? Isn't that an example of altruism that evolution would eliminate from the gene pool? Jo Handelsman, a bacteriologist who studies soil bacteria interactions in the department of plant pathology at University of Wisconsin-Madison, studies Bacillus cereus, a close relative of B. anthracis -- anthrax.

She says bacteria release chemical signals saying they are able to transfer genes, a signal to which others respond. That makes swapping a win-win solution -- the donor bacterium keeps the original and passes along a copy of the plasmid.

Small white oval bacteria against black background. A scanning electron micrograph of B. cereus spores. The bacterium is common in the natural environment and in a variety of foods. Structurally a very close relative to B. anthracis, some strains of B. cereus are able to cause foodborne illness.
Courtesy Jo Handelsman, Dept. of Plant Pathology, University of Wisconsin-Madison.

Plasmid transfer, Handelsman adds, is an evolutionary advantage because it allows bacteria to constantly change their genomes. "This allows them to respond to their environment better, since the more variation, the more material there is for natural selection to act upon."

Beyond antibiotic resistance, plasmids can truck around other handy talents like the ability to degrade -- eat -- various food sources, she adds. "There are weird carbon sources that you would not expect bacteria to degrade, but some will have the ability and transfer it to other bacteria through this sexual process." (It's sex without reproduction, she notes, where genes are transferred without the cell dividing. In contrast, multicellular organisms use sex to move genes and reproduce.)

Slo, Nellie!
Back to our story. Nobody has seen anthrax acquire antibiotic resistance via the dangerous plasmid route -- perhaps because the disease was not a front-burner issue until last month. However, related bacteria do get antibiotic resistance through plasmids.

If the evolution of antibiotic resistance is an inevitable fact of life, can we slow it? Evolutionary biologist Stephen Palumbi suggests using our knowledge of evolution to fight back. He notes that current guidelines for treating tuberculosis, caused by a highly drug-resistant bacterium, call for really squashing the bugs -- since the ones that survive early treatment are by definition at least partly resistant:

Test the bug to see which drug is effective
Use multiple drugs from the outset to make sure all bacteria die
Treat long enough to kill the lingering, partly resistant bugs
Make sure patients take their meds -- even after they feel better -- until the bug is cooked.

So, without second-guessing the idea that people who may have been exposed to anthrax need antibiotics, what are the long-run dangers of widespread use of the drugs? For one thing, notes the Alliance for the Prudent Use of Antibiotics, antibiotics can kill benign microbes, altering the microbial balance in your body.

It's a little-known fact: Benign bugs can keep nasties in check by simply out-competing for resources.

More dangerous is the threat that the drugs will lose effectiveness. People who grew up in the antibiotic age never knew the horrors of tuberculosis, typhus, leprosy, plague and various other bacterial infections.

And antibiotic resistance is not just a threat while treating anthrax or another killer. Even if an antibiotic selects for resistance only among the benign bugs in your gut, that resistance could, through gene-swapping, wind up in a deadly bacterium.

Black, rice-shaped bacteria against blue background. A micrograph of B. cereus, a bacterium that is common in the natural environment and in a variety of foods, showing a mixture of vegetative cells and spores. Structurally a very close relative to B. anthracis, some strains of B. cereus are able to cause foodborne illness and some protect plants from disease.
Courtesy Jo Handelsman, Dept. of Plant Pathology, University of Wisconsin-Madison

That's one of many reasons authorities warn that we are turning the clock back to a more deadly time. Since the 1940s, when antibiotics first entered widespread use, Handelsman says, "We have gotten complacent about bacterial disease. We are moving into an era when we will no longer be able to treat bacterial diseases -- back to 19th century medicine."

Although the issue may be especially piercing to Handelsman, who lost her mother to a drug-resistant bacterium, she's hardly alone in raising the caution. In the future, she says, "Everyday things like infections associated with surgery or burns, or common ear infections, strep throat and pneumonia, will suddenly become life-threatening."

-- David Tenenbaum (with a thank-you for research help from University of Wisconsin-Madison microbiology grad student Christian Riesenfeld).



Isolation of Antibiotic Resistant Salmonella From Retail Ground Meats, David White et al, New England Journal of Medicine, 18 Oct. 2001, pp. 1147-54 (See also pp. 1155-60, 1161-6, 1202-3)..
  Credits | Feedback | Search

©2001, University of Wisconsin, Board of Regents.