Pharmaceutical And Biotech Firms Taking On Drug-Resistant Microbes

Drug-Resistant Microbes As pesky pathogens continue to evolve, new technologies to combat them are emerging, spelling job opportunities for molecular biologists and chemists. OBSTINATE MICROBES: Margaret Rennels cites strains of pneumococcus resistence to two major drugs. At drug and biotech companies across the United States, scientists have set their sights on a most elusive target: drug-resistant microbes. Working in pharmaceutical- biotechnology partnerships, researchers are trying every trick in the book-including high-tech drug discovery, genome sequencing, and development of new vaccines-to overcome resistant pathogens. In addition to saving lives, successful companies stand to gain a significant share of the $23 billion antibiotics market. It's an alluring combination. "In our long-term strategy, everything we're doing now is based on [disease] resistance," remarks William Kohlbrenner, manager of infectious diseases at Pfizer Inc. in New York. That sentiment is echoed throughout much of the pharmaceutical industry, he adds. A handful of new or improved antibiotics geared to resistant bugs are in various stages of clinical trials, and ideas for novel therapeutics abound. These efforts bring job opportunities to microbiologists, particularly at expanding biotech companies. One hot job prospect: bioinformatics specialists, or biology-trained researchers who wield computers to find and decipher resistance-related genes. These genes lie within human and bacterial genomes currently being sequenced in various large-scale projects. World Health Organization, May 1996: "The gap between [microbes'] ability to mutate into drug-resistant strains and man's ability to counter them is widening fast." "We're going to be inundated by a flood of genomics data," predicts Frank Tally, research director at Cubist Pharmaceuticals, a private company in Cambridge, Mass. To determine relevant genes from those data, an investigator must be well-versed in assay development and genomics, he says. Drug-resistant microbes figure prominently among public health worries. According to a newly released World Health Organization (WHO) annual report, "The World Health Report 1996," drug-resistant strains of microbes have evaded common treatments for tuberculosis (TB), malaria, cholera, and pneumonia. "The gap between [microbes'] ability to mutate into drug-resistant strains and man's ability to counter them is widening fast," the WHO report warns. According to statistics from the Atlanta-based Centers for Disease Control and Prevention (CDC), 44 percent of infections that patients get in hospitals are caused by four bacteria: staphylococci, enterococci, pneumococci, and pseudomonades. Various strains of these bacteria have become resistant to all but a few antibiotics. By simple Darwinian selection, bacteria and fungi evolve ways to survive in the presence of drugs. A bacterium, for example, can develop enzymes that destroy antibiotics; activate cellular pumps to flush drugs away; or change shape, knocking away an antibiotic that previously bound to and disabled the microbe. Because bacteria rapidly multiply, they have ample opportunity to mutate or share DNA. Ironically, the success and widespread use of antibiotics contribute to drug resistance. Scientists think the longer bacteria are exposed to a drug, the more likely they are to evolve a way around it. Today, 160 antibiotics-all based on a few basic chemical structures-are on the market. Researchers suggest these drugs may be overprescribed. What's more, patients often fail to complete antibiotic therapy; they stop taking drugs as soon as they feel better. Bacteria still in the body can rebound, developing resistance to the drug at hand in the host's system. Such misuse of prescriptions, combined with societal conditions-such as the growth of day-care centers and increased long-term care in hospitals-provides an environment where drug-resistant microbes can emerge and thrive. "It is an enormous problem," says Stuart Levy, who heads the Center for Adaptation Genetics and Drug Resistance at Tufts University School of Medicine. "We hope new and improved therapeutics will be here by the next century." In the 1940s, penicillin, the first modern antibiotic, was a wonder drug. During World War II, penicillin cured countless bacterial infections in a matter of days. Amid much corporate fanfare, Pfizer produced more than half the penicillin used during the war. For antibiotics, times were good. Research Effort Loses a Key Contributor When asked about the scariest drug-resistance scenario, researchers typically point to one antibiotic: vancomycin. This is one of the most powerful antibiotics in a physician's arsenal-and one of the few still effective against most drug-resistant bacteria. If many microbes grow to evade vancomycin, researchers warn, a host of diseases could become untreatable. 'UNACCEPTABLE LOSS': Vancomycin resistance researcher Sandra Handwerger died on April 15 at the age of 41. Scientists are intensely studying how bacteria grow resistant to vancomycin. On April 15, the science community lost an important contributor to this effort: Sandra Handwerger, an assistant professor of microbiology at Rockefeller University in New York. At 41, Handwerger died of breast cancer. "It is really an unacceptable loss," says Alexander Tomasz, a Rockefeller microbiologist and head of the lab in which Handwerger worked. "During the last year, she really became accepted as one of the top handful of scientists working on vancomycin resistance." Daniel Sahm, a pathologist at Washington University in St. Louis, recalls that Handwerger loved research and added to the camaraderie of the community. "Sandra was a wonderful person to work with, and I think her success as a scientist can be attributed to a great willingness to collaborate," Sahm comments. Together, Sahm, Handwerger, and colleagues showed for the first time how a critical vancomycin resistance gene is "turned on" by a chemical precursor (D.F. Sahm, L. Free, S. Handwerger, Antimicrobial Agents and Chemotherapy, 39:1480-4, 1995). Handwerger had been at Rockefeller since 1992. Before that, she held positions at Beth Israel Medical Center and Mount Sinai School of Medicine in New York. She earned an M.D. from Columbia University College of Physicians and Surgeons in 1980. Sadly, Sahm says, Handwerger was beginning to unveil important insights into vancomycin resistance when she passed away. "She got taken away just as her career was taking off." -K.S.B. But behind the applause, evolution was quietly carrying on. Within four years of penicillin's mass production, some bacterial strains stubbornly refused to succumb to the drug. Ever since, drug companies have fought resistance problems one-on-one. If, for example, a bacterium creates an enzyme to digest an antibiotic, researchers might give physicians two drugs: the original antibiotic, plus a drug to short-circuit the resistance enzyme. By definition, this approach is reactionary. Scientists administer a drug, wait for a bacterium to develop resistance, and then recycle an improved version of the drug. Now, companies like Pfizer are using gene technology and automated drug screening to present an offensive, rather than defensive, strategy. "We're transitioning from modifying known agents to getting into novel chemical series," Kohlbrenner says. "We think developing novel agents that these bugs haven't seen before is the way to go." To find new drugs and microbe targets, pharmaceutical companies-including Pfizer, Abbott Laboratories Inc. in Abbott Park, Ill., and Schering-Plough Corp. in Madison, N.J.-are partnering with biotech firms. In March, Pfizer struck a deal with Microcide Pharmaceuticals Inc., a Mountain View, Calif., biopharmaceutical company that's about to go public. Pfizer agreed to provide up to $32 million to Microcide, which is searching through bacterial genomes for genes essential to a microbe's survival. One idea: By knocking out, or disabling, essential genes, researchers can prevent a bacterium from developing. Similar work is under way at Genome Therapeutics Corp., a public company in Cambridge, Mass. Collaborating with Schering-Plough in a deal potentially worth $43 million, Genome Therapeutics plans to sequence the entire genomes of certain resistant bacteria, determining each gene's function by comparing its structure with that of known genes. Again, genes pivotal to a pathogen-say, those needed to build proteins-will become targets for drug intervention. "In the past, over 100 antibiotics were developed, directed at just 15 [molecular] types of targets," says Gerald F. Vovis, senior vice president of pathogen genetics at Genome Therapeutics. "Now, we can uncover all the genes that exist in an organism. If you have genetic information and a way to screen for biological relevance, you have a large number of targets at your disposal." In addition to genomics, combinatorial chemistry and high-throughput drug screening (K.S. Brown, The Scientist, May 13, 1996, page 1) lead the biotech revolution in the search for new antibiotics, notes Neal Farber, vice president of corporate development at Cubist. "For decades, antibiotics [were] the domain of large pharmaceutical companies using existing empirical approaches," Farber points out. "Now, cutting-edge tools in molecular biology are letting us [at biotech companies] see things through a new light. Cubist has already validated some novel antimicrobial targets in its screening." And that's where new jobs come in. Both Cubist and Genome Therapeutics are currently hiring researchers. The companies report that creative microbiologists with a knack for computers are in high demand. "Generally, it's going to be a younger person, maybe someone in their 30s-a person who's grown up with computers," Vovis comments. For these people, "there's tremendous opportunity," he believes. Several companies hope to get a jump on resistance before it becomes a problem with fungi such as Candida and Cryptococcus. RiboGene Inc., a privately held biotech company in Hayward, Calif., is working to discover small molecules that will disrupt RNA translation in pathogenic fungi. In the past, bacteria researchers have used this strategy to create erythromycin and tetracycline, two phenomenally successful antibiotics. PLAN OF ATTACK: Charles Moehle of RiboGene says his company is using assays to screen compound libraries for potential antifungal drugs. So far, fungi have not displayed drug resistance as boldly as their bacterial counterparts. But drug-resistant fungi could become a problem in immunocompromised patients, such as those with HIV or those undergoing organ transplants. Potential resistance is exacerbated by the fact that relatively few antifungal drugs exist, explains Charles Moehle, head of the antifungal program at RiboGene. "Our view is that it's important in the fungal field to hit new targets," Moehle says. "Most current drugs hit the same biochemical pathway, so a pathogen that's more resistant in that pathway is going to be hard to treat. Our idea is to attack a different range of pathogens." In an approach similar to that taken by other biotech companies, RiboGene is using an array of assays to screen compound libraries for potential antifungal drugs. In April, the company announced a collaboration with Abbott to pursue fungal targets. Two private biotech companies in Cambridge, Mass.-Myco Pharmaceuticals Inc. and Mitotix Inc.-also are pursuing antifungal compounds with a resistance angle. Some scientists wish the antimicrobial industry would sink more research into cost-effective vaccines. In many cases, disease prevention via vaccines could preempt the drug-resistance problem, according to Margaret Rennels, a pediatrics specialist with the University of Maryland School of Medicine's Center for Vaccine Development in Baltimore. One example: about half the strains of the bacterium pneumococcus-which causes pneumonia, ear infections, and meningitis-are resistant to penicillin, physicians' first choice for fighting these ailments. Some of these strains also are resistant to a class of drugs called cephalosporins, a doctor's second choice. If your child has a strain that is resistant to both of these, then vancomycin [another antibiotic] is the last choice," Rennels says. She notes that vancomycin is not an ideal antibiotic. For one thing, it doesn't penetrate the brain well, so it's not as effective against meningitis. Moreover, physicians typically avoid vancomycin because of its severe side effects. It appears to be just a matter of time before pneumococcus gains resistance to vancomycin as well-leaving doctors without any effective antibiotic (see story on page 8). "So the need for a pneumococcal vaccine that works in kids becomes very critical," Rennels remarks. At the combined meetings of the American Pediatric Society, the Society for Pediatric Research, and the Ambulatory Pediatric Association in May, Rennels announced results from a series of trials for a pneumococcal vaccine developed by Wyeth-Lederle Vaccines and Pediatrics, a business unit of Wyeth-Ayerst Laboratories in Philadelphia. The vaccine, which began Phase III clinical trials last fall, seems safe and effective. The company must further demonstrate efficacy before submitting the vaccine for final FDA approval. Merck and Co. Inc. of Whitehouse Station, N.J., also is developing a pneumococcal vaccine for children. Such a vaccine now exists for adults, but it is ineffective in children less than two years of age. "It is our hope that the new vaccine will take care of a good portion of the resistance problem with pneumococci," Rennels says. Vaccines are an option that should not be forgotten, she adds. Despite differing approaches toward resistant microbes, researchers agree on one thing: These bugs are tenacious. Scientists are still unraveling the molecular mechanisms of resistance. Some now are cautioning, for example, that bacteria may be able to maintain resistance levels even if physicians and consumers cut back on antibiotic use (S. Schrag, V. Perrot, Nature, 381:120-21, 1996). Others worry about a "window of vulnerability," a time when microbes resist all current drugs, yet new drugs are still under development. "Particularly in the context of hospital infections, I think we are facing this gap," comments Pfizer's Kohlbrenner. "We may have a very serious situation." One often-cited example is TB. Once considered a plague of the past, TB roared back as public health efforts against the disease dwindled. For example, New York City Department of Health commissioner Margaret Hamburg and others were stunned to find that TB rates in the city nearly tripled from 1978 to 1992. During that time, drug resistance among new patients increased from 10 percent to 23 percent (T.R. Frieden et al., New England Journal of Medicine, 333[4]:229-33, 1995). Thanks to a renewed emphasis on fully completed therapy, TB rates appear to be dropping. In the end, Vovis says, companies face a potentially endless race to outsmart-or just keep up with-evolving microbes. "Organisms may take a while to develop new resistances, but they certainly will," he states. "It will keep the molecular biologists and chemists employed for a long, long time." Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

Pharmaceutical And Biotech Firms Taking On Drug-Resistant Microbes

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