War Against The Microbes

As deaths from infections surge, medicine is racing to regain control over superbugs

One of the greatest triumphs of human ingenuity has been our progress against infectious disease. Today, we have only the mute testimony of millions of gravestones to remind us of the lives tragically cut short by scarlet fever, polio, smallpox, or rampant infections of childbirth. But these mighty conquests are of small comfort to Christy and Chad Gimmestad of Evans, Colo. Their 16-month-old daughter, Anna Grace, died in late 1996 during a worrisome outbreak of E. coli 0157:H7, a vicious microbe unknown until 1980. E. coli's rampage continues: It sickened 16 people in Colorado last year.

Nor is the miracle of penicillin and other antibiotics much consolation to the families of the 33 people who have died of rampaging strep A infections since December in Texas. And our successes treating the terrible lung disease tuberculosis may not have much meaning for California teenager Debi French. In 1993, French came down with a TB infection potent enough to fight off even today's miracle drugs. Only after a two-year struggle--and the surgical removal of nearly half of her right lung--did the high-schooler come out on top in this battle of humanity vs. the microbes. On Mar. 18, the World Health Organization warned that TB could infect 1 billion more people in the next 20 years.

The sobering truth is that while we have won many such battles, the war is still raging. But now, researchers are rearming. After a decade of relative inaction, pharmaceutical companies have stepped up their efforts to find new drugs, vaccines, and other treatments to knock back the microbial hordes. "We're seeing the tide shift dramatically," says James F. Young, senior vice-president of research and development at MedImmune Inc. in Gaithersburg, Md. "Industry is jumping into antibiotics and vaccine development with everything we've got."

GRUESOME DEATHS. That may be a bit overstated. Research on infectious diseases still lags efforts on, say, heart disease. But any progress is urgently needed. Scarcely a week goes by without a report of some dire and growing threat. Mysterious hantaviruses are causing gruesome deaths in the West. Potent new forms of TB are emerging in Tennessee and Kentucky. Staph germs that don't respond to the most commonly used antibiotics are spreading from Chicago hospitals to the surrounding community.

In fact, more than 30 dangerous new infectious agents have been discovered in the past two decades. The death rate in the U.S. from infections jumped nearly 58% between 1980 and 1992, mostly because of AIDS and an aging population, which is more susceptible to germs. Researchers estimate that hospital-acquired infections alone are responsible for a staggering $4.5 billion in annual U.S. health-care costs.

The situation is far grimmer elsewhere. With malaria, TB, and dengue fever on the rise, microbes are now causing one-third of the world's 50 million-plus deaths each year. "We are seeing a global resurgence of infectious diseases," U.S. Surgeon General David Satcher warned Congress on Mar. 3.

TURNING POINT. Experts say humanity is now at a crucial turning point in the millennia-old war against microbes. One reason is the explosion in world population. Another is air travel--the deadliest infectious diseases are only a plane ride away from New York, London, or Tokyo.

Most ominously, though, microbes have been hard at work in a deadly race, mutating to create potent new defenses far beyond the reach of many existing treatments. "We have never been more vulnerable," says microbiologist and Nobel laureate Joshua Lederberg. "When I go through all the adaptations [made by] the microbial world to make a living at our expense, I sometimes wonder how we're still here."

But microbes aren't the planet's only wily species--and humanity is fighting back. One part of the solution is to beef up global surveillance and respond faster to diseases, squelching outbreaks before they explode into epidemics. A second is boosting prevention. On Mar. 19, for instance, Agriculture Secretary Daniel R. Glickman unveiled a plan for dousing chickens with harmless bacteria so the "good" bugs will prevent disease-causing salmonella from contaminating poultry flocks.

The final piece of the puzzle is the development of new drugs and vaccines. Drugmakers around the globe sharply curtailed efforts to develop new antibiotics in the 1980s, deciding the market was crowded and satisfied. "They forgot a few minor things," says Dr. David M. Shlaes, vice-president of infectious disease research at American Home Products' Wyeth-Ayerst Research unit. "Namely, resistance." Now top researchers at Wyeth-Ayerst, Pfizer, Abbott Laboratories, Merck, SmithKline Beecham, Glaxo Wellcome, Schering-Plough, and a host of biotech companies are launching an assault against infectious disease.

The counterattack is by no means comprehensive--efforts directed against the world's biggest killers, such as TB and malaria, are disappointingly small. But there is hope for a slew of new and better drugs and vaccines against everything from pneumonia and staph to flu and hepatitis. According to the Pharmaceutical Research & Manufacturers of America, 125 drugs aimed at infectious disease were in the pipeline in 1996, up from just 79 two years earlier.

Fueling the hope for better treatments are rapid advances in technology that speed up drug discovery. Robotics and high-speed equipment allow researchers to test thousands of compounds against a disease target in one day. And the gene-sleuthing revolution has made it possible to finally understand what makes bugs tick--and how to attack them at their most vulnerable points. "We are stripping these beasts bare, exposing their genetic secrets, and turning that information against them," says Alan R. Proctor, an executive director of research at Pfizer Inc.

Advances are already saving lives. On a spring day in 1993, Dr. James J. Rahal at The New York Hospital Medical Center of Queens was in a panic. His patient, a 46-year-old woman, had developed a life-threatening infection in a major artery after vascular surgery. Doctors tried six different antibiotics. None worked--not even Vancomycin, usually the superdrug of last resort. "Chances are that she would have died," says Rahal. Fortunately, a colleague had read about an experimental drug, Synercid, being developed by Rhone-Poulenc Rorer Inc. in Vitry-sur-Seine, France. Rahal got on the phone: Could Rhone send him the drug immediately?

JUST IN TIME. In France, Rhone scientist Francois Bompart swung into action, wresting permission from the U.S. Food & Drug Administration to ship the drug to New York. Rahal rushed to inject it into the patient--just in time. Synercid completely wiped out the Enterococcus faecium in her system. Since then, the drug has been given to more than 3,000 patients on an emergency basis, and an FDA committee recently recommended that the drug be approved quickly. "This is one victory in the war against bacteria," says Rhone's Gary T. Shearman, who oversees drug development. "But we need all the weapons we can get."

The search for new weapons has led some companies to reconsider candidates once rejected. At Schering-Plough Corp., an antibacterial chemical called Ziracin had been kicking around for more than a decade. But Schering set it aside because it proved too toxic in many patients. Remembering how potent the drug was, Schering began to give it another look three years ago. Tests showed that a new, less toxic intravenous form wiped out more than 5,000 different strains of bugs. Now, company scientists are racing to do larger tests of its safety and effectiveness in people. Dr. Lisa Dever, head of the infectious diseases clinic at the East Orange (N.J.) Veterans Affairs Medical Center, has done some tests of Ziracin and describes the results so far as "nothing short of amazing."

Other companies are employing clever strategies to outwit drug-resistant bacteria, thus prolonging the usefulness of existing weapons. Killer microbes such as staph have evolved the ability to dice up penicillin and pump out tetracycline before either antibiotic has a chance to work. But what if doctors could add another drug that attacks the defense system? That would enable the original antibiotic to still fight the infection. Microcide Pharmaceuticals Inc., in Mountain View, Calif., is developing a compound with Daiichi Pharmaceuticals U.K. Ltd. to do just that. Their drug cripples the antibiotic pump used by the bug, Pseudomonas aeruginosa, which causes lung infections. Wyeth-Ayerst is working on a new form of tetracycline that can get around the defense mechanisms of bugs like enterococci.

But shoring up old drugs may only buy a little time. What's urgently needed are new classes of compounds that attack bugs in new ways. First on the scene are likely to be antibiotics called oxazolidinones. These were discovered by DuPont Co. in 1987 the old-fashioned way--researchers dumped chemicals onto bacteria and waited to see if the bugs died. Scientists subsequently learned that the oxazolidinones kill bacteria in a way that's completely different from any existing drug. These compounds seem to gum up the work of a cell's protein-making factories at a different location than do other drugs. Researchers at Pharmacia & Upjohn Inc., which has such a drug in final tests, hope that because the bacteria haven't seen this avenue of attack before, they will be slow to develop a defense.

The company plans to file a new drug application on the oxazolidinone antibiotic as early as 1999. Bayer AG Group is also working on such a drug, and Dr. Stefan Wohlfeil, head of anti-infectives research at Bayer, says he's keeping his fingers crossed that unexpected problems don't crop up. "If anything happens to this class," he warns, "there isn't much on the near horizon."

The more distant horizon, however, is bursting with promise--thanks to a revolution in molecular biology. Researchers have learned to decode the entire DNA sequences of lethal microbes. That makes it possible for scientists such as Dr. Francis P. Tally at Cubist Pharmaceuticals Inc. to uncover the biological pathways that pathogens need to survive. "Bacteria are no longer black boxes," says J. Craig Venter, president of the Institute for Genomic Research (TIGR), the Rockville (Md.) laboratory that has led the way in microbial gene sequencing. "It's like going into a dark room and turning on the light switch."

That light, however, can be blinding. The first microbe whose entire genetic sequence was decoded by TIGR researchers was Haemophilus influenzae, a cause of ear infections and meningitis. It contains 1,740 genes; others have even more. It's a huge amount of information--the trick is figuring out which pieces are important. "It's like going into a Russian library when you don't speak Russian," says Kelvin Cooper, a director of medicinal chemistry at Pfizer Inc. In labs of both big drugmakers and small biotech operators, PhDs hover over computers, crunching the mounds of data generated by the genetic sleuthing. Comparing well-understood gene sequences from other organisms to those of the bugs, they look for similarities. That gives a clue to what certain genes do--and where the microbe's defenses are weakest.

DISARMING. Consider the tale of tRNA synthetase, one in a long list of possible drug targets. It is an enzyme used to shuttle around amino acids, the building blocks of proteins. There is a different tRNA synthetase for each of the 19 amino acids. Prevent any one of them from doing its job, and wham!--the whole cell shuts down.

Back in the late 1970s, SmithKline scientists figured out that an existing drug, Bactroban, kills Staphylococcus aureus bacteria by gumming up one of those enzymes. In 1994, genetic sleuthing helped the company identify the other 18 tRNA synthetases in staph aureus and 19 previously unknown genes and enzymes in Streptococcus pneumoniae. "All of a sudden, we had 19 new targets for drugs," marvels Martin Rosenberg, head of anti-infectives research at SmithKline. The company has launched a major screening program to find drugs capable of blocking all the new targets.

A completely different tack is to search out microbial genes responsible for disease. When they're just drifting through the air, lethal bugs activate only the genes they need to live. But when they find a juicy human to infect, they turn on genes that make toxins, ward off the immune system, and otherwise wreak havoc. Some of Microcide's scientists are searching for these "virulence" genes--and for drugs to block them. "We are looking for ways to disarm the bacterium rather than kill it," says CEO James E. Rurka.

Researchers are also looking for new drugs to attack viruses. There, the hard-won lessons of HIV may pay off against scourges such as hepatitis B and C, which, combined, infect 360 million people worldwide. Drug companies already know that by blocking HIV's reverse transcriptase enzyme they can stop the virus from copying itself, and they are going after the same target in hepatitis. Glaxo Wellcome PLC is expected to launch its AIDS drug lamivudine for hepatitis next year, and Bristol-Myers Squibb Co. is beginning the final phase of clinical trials on a drug called lobucavir for use against hepatitis B and cytomegalovirus, a common infection striking HIV patients. James R. Merson, who, along with Timothy R. Rolph, is leading Pfizer's charge against viruses, notes: "The success we've had with HIV bodes well for what we should be able to do against other viruses."

Perhaps the best way to conquer viruses, however, is by preventing infection with vaccines. Companies are still more than a decade away from an AIDS vaccine. But for other diseases, the new genetic information is leading to rapid progress. The old-fashioned way of making a vaccine is to grow a virus and then kill or weaken it. When administered, the dead or impotent virus prods the immune system into making protective antibodies. But the approach can be too slow or costly to counter a sudden epidemic. Protein Sciences Corp., based in Meriden, Conn., is using a more sophisticated approach. Its researchers have isolated an influenza virus protein that plays a key role in helping the virus attach to other cells. Injecting the protein into the body prompts the formation of antibodies that keep the virus from attacking cells. Tests at the Agricultural Research Service lab in Athens, Ga., show that the vaccine can protect chickens against the avian flu strain that paralyzed Hong Kong last year.

It will be years before many of these research efforts produce vaccines and drugs in the never-ending war on microbes. It doesn't help that the research effort in industry, while impressive, falls far short of what most public-health experts would like. The problem is economics. The antibiotics and vaccines developed in the 1950s, '60s, and '70s are so cheap and still so effective in most cases that the markets for new treatments are uncertain.

Moreover, there are troubling holes in drugmakers' counterattack. The developing world can't afford most drugs. That means the greatest scourges are largely ignored by industry. One of these, malaria, infects 500 million people and cripples economies from sub-Saharan Africa to Southeast Asia. Another, TB, kills 3 million people per year.

Some progress has been made against tuberculosis. An improved anti-TB drug from Hoechst Marion Roussel Inc. is being reviewed by the FDA. And Glaxo Wellcome has signed an agreement with researchers at Albert Einstein College of Medicine to develop a drug that is effective against TB strains resistant to other antibiotics. Still, TB, like malaria, attracts fewer resources than other infectious diseases. And it's not hard to figure out why, says Gail H. Cassell, who oversees Eli Lilly & Co.'s infectious disease research: "There's been the least effort to develop new anti-infectives [against these diseases] because of the inability of the population in the most affected areas to pay."

That's just one reason the war with microbes may never be fully won. Companies and nations need to launch--and maintain--effective campaigns not only against strep and flu but also against the scourges that ravage far too many of the world's people. Only then would we have a chance of relegating these killers to the pages of our history books.

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