College of LAS « Illinois

Research

Good Bacteria Gone Bad

Freewheeling bacteria "sex" is one reason that antibiotics are losing their effectiveness at an alarming rate.

Salyers

The scene playing out in the vials in Abigail Salyers' laboratory is like a singles bar for bacteria. Cells are coupling promiscuously, exchanging a little DNA, then moving on to their next encounter.

"The cells don't even need to establish contact to exchange DNA," says Salyers, a microbiologist at U. of I. who has tracked the antics of these one-celled organisms for 35 years. "If a cell bursts, the contents may be released into the surrounding environment and taken up by other bacteria."

There are other ways, too, that bacteria can take up genetic material and, basically, modify their ability to survive.  And that's the point that the 63-year-old Salyers is trying to make. Bacteria's ease in exchanging genes is at the heart of what she and a growing number of scientists and healthcare professionals see as an emerging threat to public health worldwide.

Since the mid-1990s, Salyers and a cadre of prominent international researchers have warned of the growing bacterial resistance to antibiotics. The drugs we have relied on for 60 years to fight once-deadly infections, and to make routine medical procedures safe, are losing their effectiveness at an alarming pace.  Aggressive skin infections, post-surgical infections, treatment-resistant salmonellosis, recurrent urinary tract and heart infections, and a 58-percent rise in infectious diseases between 1980 and 1992 are all linked with bacteria resistant to treatment.

A decade later, people are beginning to heed the warnings. Salyers' revelations about the promiscuity of bacteria are an important part of that. So is her determination in making people aware of the danger we face if cures are lost.

The danger is real and insidious, according to Salyers. "We won't wake up tomorrow and be cast back into a bacterial-disease-ridden world," she says. "But unless we take action, the danger will sneak up on us."

Mounting Evidence for a Loss of Cures

According to the U.S. Food and Drug Administration, 70 percent of bacteria that cause infections in hospitals are resistant to at least one antibiotic used to treat them. In addition, superbugs—strains resistant to multiple antibiotics—are emerging as even greater threats. Even tuberculosis is now resistant to multiple antibiotics.

Forty-one percent of strep infections today are resistant to penicillin, while 15 percent are resistant to three or more antibiotics. This virulent pathogen, Streptococcus pneumoniae, is responsible for illnesses ranging from middle ear infections to pneumonia and meningitis. It is also the main cause of death of people initially infected with the influenza virus.

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Of the estimated 2 million patients each year who develop infections while hospitalized, 90,000 will die, mostly from staph infections, which are now resistant to penicillin, methicillin, and other standard antibiotics, according to data from the Centers for Disease Control and Prevention (CDC). The drug of last resort, the powerful antibiotic vancomycin, may soon be rendered ineffectual in some cases. This past May, doctors reported the first case of vancomycin-resistant staph.

Because hospitals are not required to report infections acquired by patients while they were hospitalized, the statistics reported by the CDC are conservative, at best.

As infection rates rise, the interest of pharmaceutical companies in developing antibiotics is decreasing—a trend with long-term implications. For example, the company that developed vancomycin in 1956—Eli Lilly—is among the major pharmaceutical companies that were once a pipeline for new antibiotics. However, Eli Lilly and other companies have abandoned the field for more lucrative alternatives.  A recent analysis of annual reports of 15 major pharmaceutical companies cited by the Infectious Disease Society of America found that only five of the more than 400 drugs in development were antibiotics.

"The incentives aren't there," says Steve Projan, assistant vice president, protein technologies, at Wyeth Research. "Why should pharmaceutical companies devote the $1 to 2 billion and average of 14 years that it takes to bring a new drug to the market on a product people are being discouraged from using? There are also a growing number of cheap, generic alternatives that people take for only a week. The companies can focus on unmet medical needs like Alzheimer's disease where the therapies are going to be lengthy and there is true blockbuster potential."

The potential sales for a new antibacterial drug is difficult to estimate since the dollar sales of antibiotics have actually dropped as generic forms of several popular antibiotics have entered markets around the world.  A new drug for fighting serious hospital infections is among the few that might have the potential of earning between $200 and $400 million per year. In contrast, an Alzheimer's drug is worth in excess of $1 billion a year alone.

staph

Discovering the root causes of resistance is where Salyers comes in. Why do some bacteria become resistant whereas others do not? Why do 60 percent of a particular strain become resistant whereas the other 40 percent remain vulnerable to bacterial antibiotics? How can we preserve existing resistance?

Staph bacteria is one of the most common sources of infections. It is also increasingly resistant to treatment with antibiotics. Of the estimated 2 million patients each year who develop infections while hospitalized, 90,000 will die, mostly from staph infections.

Gene Swapping, or How Resistance Is Incurred

Bacteria have been evolving for 3 billion years. Most bacteria reside harmlessly on your skin or in your intestines. But they may turn virulent when they gain access to other regions, such as through a wound or during a medical procedure. "Just as a weed is a flower in the wrong place," says Salyers, "a bacterium that escapes the colon into a different organ or tissue can cause serious injury."

Since a serendipitous discovery by Alexander Fleming in 1928 gave the world penicillin, the discovery of other molds, fungi, and natural organisms capable of interfering with these microbes' ability to reproduce have tamed virulent bacteria.

Some antibiotics impair the production of a key protein, while others disrupt the formation of cell walls. By one means or another, resistant bacteria eliminate the drug's target in the bacteria.

Scientists once believed that resistance in bacteria was primarily acquired through mutations. But this process is relatively slow and risky.  And a mutation can kill a bacterium.  A more expedient way for the bacteria to acquire resistance, scientists now know, is by swapping genes.

This phenomenon had been demonstrated in labs in the 1950s. However, no one knew if it occurred in nature. Then, in 1990, Salyers released the results of a two-decades-long study that focused on a bacterium that had been largely ignored by scientists. Her landmark study provided the first evidence that not only was gene swapping common among bacteria, but it was also happening with shocking ease.

Begun in 1970, the study tracked resistance genes in isolates of Bacteroides, a relatively benign bacterium that accounts for a quarter of all intestinal bacteria. Little was known about it at the time because, as an anaerobe, it required an oxygen-free environment to study it.  And since it was not widely studied, none of the sophisticated genetic techniques then becoming available were designed to work with it.

Salyers

Salyers came to microbiology from theoretical physics and, hence, was unaware of the bacterium's underdog status when she joined one of the few research teams that was studying anaerobic bacteria. That team was investigating the possible role of Bacteroides in colon cancer, and the researchers used antibiotic resistance genes as markers. Salyers found herself intrigued with how these resistance genes were being passed around. Her curiosity led to another question: Could these bacteria pick up resistance from other bacteria that were passing through the gut?

The isolate study was designed to address that question. Using bacterial samples collected from hospital patients, her team began tracking the increase in the number of genes resistant to the antibiotic tetracycline in distantly-related species of Bacteroides.

In 1970, 30 percent of the genes in their samples were resistant to tetracycline. By 1990, 80 percent of the genes had acquired resistance. Because of the genetic distance among the samples, the only way the bacteria could have acquired resistance was by swapping genes.

"What we soon realized," says Salyers, "is that your colon is like a singles bar. Bacteria are passing around DNA like there is no tomorrow."

Studies that followed, by Salyers and others, showed the dramatic extent of the swapping. They discovered that bacteria could swap genes with completely different species of bacteria—a genetic exchange as dramatic as a frog sharing genes with a beetle and teaching it to croak. Bacteria could also transmit more than one resistance gene in a single encounter. Studies were done in clinical and community settings, and with other resistance genes.

More recently, Salyers' team discovered that gene swapping is actually stimulated, in some cases, 100- to 1,000-fold by tetracycline. "It's like an aphrodisiac for bacteria," says Salyers. "It doesn't just select for resistant bacteria, it actually triggers the transfer of a particular type of element, which can carry resistance genes."

After bacteria acquire resistance genes, the genes persist. Their numbers decline once a person is no longer exposed to the antibiotic, but sufficient populations of resistance genes are retained that their numbers rebound if the antibiotic reappears.

Safe Sex for Bacteria

The ability of harmless bacteria to be carriers of resistance and for the colon to act as a conduit for resistance genes is one reason that the widespread use of antibiotics, even in agriculture, presents a danger.  Antibiotics used to treat and promote growth in farm animals have been found in the food supply and in humans.

What is missing, says Salyers, who has testified before Congress and the Federal Drug Administration on these issues, is the "smoking gun" confirming that the movement is from farm animals to humans instead of the reverse.

On the human front, the Centers for Disease Control and Prevention estimate that one-third of antibiotics prescribed for humans are unnecessary. Even when antibiotics are prescribed properly, they can foster the growth of resistance bacteria for up to six months in people taking the prescription as well as those they contact.

Antibacterial soaps and household products, which have gained popularity over reliable soaps and detergents, are culprits, too. They tend only to kill harmless bacteria, thus encouraging virulent strains to get a foothold.

The danger from antibiotic resistance is real, but so are solutions. It may be possible to target the gene transfer mechanism or, someday, create compounds that rid problematic bacteria of the gene transfer mechanism.

More immediately, Salyers hopes her research will cause physicians and the agricultural community to rethink how and which antibiotics they administer.  With some antibiotics, higher dosages for shorter times may be wiser than small dosages for a long time.  Also, whether they are administered orally or topically has vital implications.  A popular acne medication was linked to fatal intestinal infections when it was taken orally because it upset the natural colonic balance of the colon. It is now administered topically. Some antibiotic usages may need to be banned.

"For the first time," says Salyers, "people are evaluating antibiotics not just for their safety but also for how they'll be administered."

There may be ways of bringing "safer sex" to bacterial orgies.

Scientists are winning some skirmishes in the battle against antibiotic resistance.
Read more in Reversing Resistance.

By Holly Korab
Fall/Winter 2005-06