Renewing the Fight Against Bacteria

In the 1940s, the mass production of penicillin led to a sensational reduction in illness and death from bacterial disease. A resulting golden era of bacterial research emerged with new classes of antibiotics, and by 1969, US Surgeon General William H. Stewart told Congress: "The time has come to close the book on infectious disease." As a result, fewer new students specialized in bacterial physiology, and federal funders shifted their focus to more immediately pressing diseases, as did many pharmaceutical companies. But while everyone forgot about the bacteria, the bacteria didn't completely abandon their unwilling hosts. Today, nearly all strains of Staphylococcus aureus, an organism that causes skin, bone, lung, and bloodstream infections, now resist penicillin. Many do the same to methicillin, and some even resist vancomycin, long considered the only uniformly effective drug for methicillin-resistant S. aureus, according to the Centers for Diseases Control and Prevention (CDC). The agency also estimates that 30% of Streptococcus pneumoniae-caused pneumonia, meningitis, and ear infections no longer respond to penicillin. In fact, about 70% of bacteria found in hospitals resist at least one of the drugs most commonly used to treat infection, according to CDC estimates. Antibiotics resistance continues to increase; much of it occurs from misuse. Physicians in the United States write about 50 million pointless antibiotic prescriptions each year for colds and other viral infections, the CDC estimates. While signs of resistance first appeared decades ago, it wasn't until the mid-1990s that medical organizations such as the American Medical Association and the American College of Physicians-American Society for Internal Medicine, provided doctors with antibiotic resistance education and guidelines to properly prescribe. Even today, "I don't think many physicians and other people are convinced that this is a problem, because they still can cure most bacterial infections, even if it takes a few tries to find the right antibiotic," says Abigail Salyers, bacterial physiologist at the University of Illinois and president of the American Society of Microbiology. Many factors increase the risk of bacterial infection and subsequent resistance, says Steve Projan, director of antibacterial research at Wyeth-Ayerst in Pearl River, NY. These factors include growing population densities and an increasingly immunosuppressed population. "People have forgotten what it was like before antibiotics: If you had Staph in your bloodstream, the infection was fatal at least 90% of the time," Projan says. Thanks to bacterial pathogen genomes, however, some pharmaceutical companies are using a target-based approach to come up with some new infection-fighting answers. Role of Basic Research Courtesy of Aventis Pharmaceuticals Alive and Well: Not all drug companies have abandoned antibiotic research as shown here in the lab at Aventis Pharmaceuticals. Scientists have left the bacterial research field in droves for newer fields including genomics and molecular biology. Meanwhile, universities have widely phased out microbiology, or merged it into other departments, leaving few faculty members to encourage young scientists into the field, Salyers says. In recent decades, the National Institutes of Health's shift to newer priorities such as viral infections and AIDS hasn't helped either. "After bacteriologists produced the molecular revolution, it was easy to think, 'well, we've done that and now we can move on.' It became unfashionable to pursue bacteria," she adds. Very little is known about the diverse genetic structure of bacteria, according to Salyers. As yet, scientists can't recognize the function of one-third of the open reading frames—the DNA region that encodes for specific proteins and bases of the coding sequence—in model bacterium Escherichia coli. Any realistic analysis of the bacterium's genome sequence is impossible, she says. Moreover, little is known about the complex mechanisms by which bacteria change and become drug resistant. Salyers' own work has uncovered how an intestinal bacterium, Bacteroides, typically becomes resistant to antibiotics through DNA transfer, not by the more widely understood mechanism of gene mutation.1 "We still have a lot to learn in the area of bacterial metabolism and physiology," confirms Rita Colwell, microbiologist and director of the National Science Foundation. It's time for an attitudinal change in the wider scientific community to recognize the importance of bacterial research, both women say. Salyers and others note that increased funding would show researchers just how important this field is. "Many scientists think that we know as much as we need to know about bacteria and that chemists and biochemists should take the lead in development of antibiotics, but there's no substitute for understanding bacterial physiology better," Salyers says. Role of Pharmaceutical Industry After decades of success in discovering antibiotics, pharmaceutical companies have struggled in recent years to find new, broad-spectrum compounds. Cost concerns and a failure to find new prospects have led Novartis, GlaxoSmithKline, Bristol-Myers Squibb Co., Eli Lilly and Co., and other major drug companies to downsize or exit the antibiotics market. Focus has shifted to developing drugs with greater potential long-term profits, particularly for treating chronic conditions such as high blood pressure. "You don't want to spend a lot of time and money developing an antibiotic and then discover after a few years that you can't use it for what it was designed to treat because of resistance," says Alan Goldhammer, associate vice president, regulatory affairs for PhRMA, the Washington, DC, representative group for the pharmaceutical industry. Not all drug companies have abandoned antibiotics, however. Antibiotics are still the second-largest drug market after cardiovascular therapeutics, and at least five such drugs earn more than $1 billion for their companies, including Cipro (ciprofloxacin hydrochloride, Bayer), Zithromax (azithromycin, Pfizer), and Augmentin (amoxicillin/clavulanate potassium, GlaxoSmithKline), Projan notes. A November 2000 PhRMA report surveyed US pharmaceutical and biotechnology industries and found 19 antibiotics currently in development. Two new ones hit the market in 2001, Invanz (ertapenem sodium) from Merck & Co. and Ketek (telithromycin) from Aventis Pharmaceuticals. The opportunity to identify novel antibacterials using a new target-based approach, founded on the sequencing of bacterial pathogen genomes, has sparked a resurgence in antibiotic research, says John Hodgson, head of infectious diseases for Aventis. "Many saw this as an opportunity to make some quick progress in developing new antibacterials, but, while genomics has provided a plethora of new antibacterial targets, it takes a long time to develop a new drug," he says. One of the first compounds to emerge from this target-based approach is a peptide deformylase inhibitor from British Biotech, which could enter clinical trials this year. Additionally, companies are seeking to develop new agents from new knowledge regarding the host response to bacterial infection, particularly those effective against sepsis, a highly fatal, hospital-acquired bacterial disease, Hodgson says. The first marketed new drug against sepsis based on this approach, Xigris (drotrecogin alfa [activated], Lilly) received Food and Drug Administration approval late last year. Government Addresses Antibiotic Resistance Courtesy of Bristol-Myers SquibbThe Enemy: Penicillin-resistant Streptococcus pneumoniae Government sources emphasize that adequate research funding is available, but only to those conducting high-quality bacterial research. The problem is that US investigation into this area just isn't robust, says Marissa Miller, antimicrobial resistance program officer with the Division of Microbiology and Infectious Diseases (DMID), National Institutes of Allergy and Infectious Diseases. "We can't just throw money at this. Then you get a lot of ... low-quality grants. You have to start small and build over time," she says. Senior level researchers, not the NIH, are responsible for jump-starting the field, she notes. They should sponsor and mentor more students while the American Society of Microbiology, NIH and NSF increase educational opportunities and grants for young investigators. Recently, the DMID announced new grants related to reducing the threat of bioterrorism. In 2000, they posted a challenge grant that partnered industry and academic scientists to study resistant infections. A 2002 partnership grant is modeled on the challenge grant, but doesn't require mandatory matching of dollars by industry. Investigator-initiated grants are always another option scientists can pursue, Miller says. Additionally, resources exist for clinical trials, animal and in vitro testing, she says. Interest is particularly high in novel approaches to bacterial therapeutics, such as phage therapy and vaccines. Moving Forward An interagency approach would help to focus funds on advancing antibacterial research, notes Miller. "If we had a Manhattan Project-type of approach, we could produce some very powerful and highly effective vaccines [and other antibacterial drugs] against a variety of infectious diseases." A 1999 Kennedy-Frist bill that identified antibiotic resistance as a looming public health problem created an interagency task force, but allocated very little new funding. Headed by the CDC, the Food and Drug Administration and the NIH, the task force issued a plan in 2000 to deal with antimicrobial resistance that includes surveillance of resistance and monitoring of drug use; prevention and control to develop better diagnostic testing and infection control and ensure appropriate use of antibiotics; research to increase understanding of microbial physiology, ecology, genetics and mechanisms of resistance; and product development to translate research into clinically useful products and stimulate development of antimicrobial products. According to Miller, not enough funds are available to fully implement the plan. Jennifer Fisher Wilson (jfwilson@snip.net) is a contributing editor. 1. N.B. Shoemaker et al., "Evidence for extensive resistance gene transfer among Bacteroides spp. and among Bacteroides and other genera in the human colon," Applied and Environmental Microbiology, 67:561-8, 2001.

Renewing the Fight Against Bacteria

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