“For Western physicians, the 1950s and 1960s were a time of tremendous optimism. Nearly every week the medical establishment declared another ‘miracle breakthrough’ in humanity’s war with infectious disease. Antibiotics, first discovered in the early 1940s, were now growing in number and potency... Medicine was viewed as a huge chart depicting disease incidences over time: by the twenty-first century every infectious disease on the chart would have hit zero. Few scientists or physicians of the day doubted that humanity would continue on its linear course of triumph over the microbes.” - Laurie Garrett in The Coming Plague1
Today such buoyant optimism is wearing thin as more bacterial strains show resistance to commonly used antibiotics. It turns out that the battle against bacterial infection is always in progress, never won.
A common expression is that bacteria capable of overcoming antibiotics have proved to be smarter than we are. They certainly are more prolific. Where a human generation may be counted as, say, 20 years, bacteria while in their "growth phase" may replicate in as little as 20 minutes. A bacterial population may thus turn over as frequently within a day as did humankind between Attila the Hun and Sir Isaac Newton. This rapid propagation puts evolution on a fast track—and among the bacterial strains emerging fit to survive are those that resist antibiotic assault.
So cracks are beginning to appear in the great wall of protection erected since the first antibiotics reached patients in the mid-20th century. Consider these reports from recent years2:
Resistant Target—Staphylococcus aureus, which appear in this image as amber beads, is a common cause of hospital infections that can be serious and even fatal. Staph began to develop resistance to penicillin in the 1940s, only a few years after the antibiotic became available. To combat resistance, methicillin was introduced in the 1960s, yet methicillin-resistant S. aureus (MRSA) soon appeared as well and is now prevalent. In addition, MRSA is being found more often in the general community, not just in hospitals. In the image here, captured by a scanning electron microscope, staph bacteria adhere to mucus amid the ciliated cells of the nasal cavity.
Credit: Juergen/Photo Researchers, Inc.
Indeed, when the World Health Organization evaluated “pharmaceutical gaps,” antibiotics topped the list, appearing ahead of gaps in therapies for AIDS and malaria and even pandemic flu.3 That ranking reflected not only the threat of drug-resistant bacterial infections but also a question about the commitment of large pharmaceutical companies to do something about them.
Extending a long tradition
What, then, is GlaxoSmithKline doing? “We are maintaining our long and productive tradition in antibiotics research,” says David Pompliano, a microbiologist at GSK. “We have contributed to the field for half a century, since our early work in semisynthetic penicillins, and we intend to contribute in the future as well. We are sustaining our long commitment.” Indeed, over the past four years, GSK has progressed more compounds as candidates for clinical studies, eight such compounds, than over the previous 20 years.
This GSK record stands in contrast to a general trend of retrenchment in antibacterial research. A task force of the Infectious Diseases Society of America has remarked that “the pharmaceutical pipeline for new antibiotics is drying up.”4 The task force goes on to say that “major pharmaceutical companies with the R&D ‘muscle’ to make progress are losing interest in the antibiotics market, even as they increase their overall R&D budgets.”
It is true that there are commercial drawbacks to the antibiotics market: the short-term use of nearly all antibiotics, and a tendency by physicians to hold back from prescribing new antibiotics so as to keep them in reserve until old standbys fail. What is more, R&D budgets must accommodate competing needs, the need for new antibiotics not being unique in being urgent. To take the US record of recent years as an example, systemic drugs for infection have accounted for about 8 per cent of all drugs brought to initial clinical studies, while drugs for cancer and immunologic disorders have accounted for more than 20 per cent.5 Would cancer patients object?
Then there are the special scientific challenges of antibacterial research. Along the trail of evolution, more of the species groupings known as genera lie between Gram-negative and Gram-positive bacteria than between humans and paramecia. A broadly useful antibiotic must be so chemically constructed as to act across this field of bacterial diversity: different molecular targets, different cell-membrane permeabilities, different metabolic pathways. It must also demonstrate an acceptable side-effect profile at the high blood levels typically required to gain penetration into bacteria cells and ensure effectiveness against the least susceptible organisms.
Clinical testing presents its own challenges, even though the course of bacterial infection is generally acute and so allows a relatively rapid assessment of antibiotic efficacy. Outbreaks of respiratory infections like pneumonia cluster in winter months, and so clinical-trial programs in all their logistical detail must chase infection between the northern and southern hemispheres. Enrolling enough subjects into studies specifically directed at resistant bacterial strains introduces further complication, since outbreaks of such infections can not be anticipated.
The data represent findings in the intensive care units of hospitals participating in a CDC surveillance program. Abbreviations here are as follows: MRSA for methicillin-resistant Staphylococcus aureus, VRE for vancomycin-resistant enterococci, and FQRP for fluoroquinolone-resistant Pseudomonas aeruginos.
Chart by courtesy of the Infectious Diseases Society of America, as derived from data collected by the Centers for Disease Control and Prevention.
Fashioning alliances and molecules
While persevering with antibacterial research, GSK is balancing its responsibilities to shareholders and society. It intends to be a good investment and a good citizen both. The company expects that prosperous nations will reward the innovation required to meet the urgent need for new antibiotics amid the accelerating spread of resistance, newly emerging infectious agents, and the menace of bioterrorism.
Where market incentives are lacking, GSK makes common cause with academia, government, and philanthropies to develop therapies for bacterial infections as well as other infectious diseases. For example, the company has formed partnerships with both the Global Alliance for TB Drug Development and the Medicines for Malaria Venture.6 Those partners help to support 55 scientists working exclusively on tuberculosis and malaria drugs. GSK contributes a like number of scientists, its laboratories, and its discovery-and-development experience. The company has committed to make resulting medicines affordable to those most in need.
The path to any new medicine is long, notwithstanding heavy investment. A decade ago, optimism prevailed that analysis of bacterial genes would yield a wealth of broadly useful targets for the antibiotics of the future. Although genomics has greatly informed microbiology, it has yet to lead to a marketed antibiotic. Nor has automated screening of bacterial targets against vast chemical libraries met early expectations: the “hit” rate in these screens—the frequency with which compounds bind to targets—has been lower than in screens for other therapeutic areas, possibly because the molecular properties to be found in current libraries are historically skewed toward mammalian targets.
Of late, GSK has made the most rapid gains in another way: Intensified chemistry. Working in tandem with colleagues in microbiology, the chemists reshape molecules into novel structures that bind in new ways to established bacterial targets. "The search for novel antibacterials is a very chemistry-intensive endeavour,” says John Elliott, a GSK chemist who works on antibiotics “Success demands perseverance."
The GSK compounds currently in the clinic represent a new class of antibiotics under evaluation for human use. Derivatives of the fungus Pleurotus mutilis7, and hence called pleuromutilins, they inhibit bacterial growth by disrupting protein synthesis. Their chemical design took a decade.
“Antibiotic discovery is not very fashionable these days,” GSK scientists wrote recently in Nature Reviews Drug Discovery, “and yet resistance has evolved to every antibiotic ever placed into clinical practice.” They continued, “Although the emergence of resistant strains is unpredictable, it is inevitable, and we must be prepared.”8
End notes
1. Farrar, Strauss and Giraux, 1994.
2. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews. Alexandria, VA: IDSA, 2004.
3. The World Health Organization. Priority Medicines for Europe and the World. Geneva: WHO, 2004. WHO/EDM/PAR/2004.7.
4. Infectious Diseases Society of America, op. cit.
5. Tufts Center for the Study of Drug Development. Impact Report. Boston, MA: Tufts University, 2006, Number 3.
6. The Global Alliance for TB Drug Development is underwritten by the Bill and Melinda Gates Foundation, the Rockefeller Foundation, the United States Agency for International Development, the Netherlands Ministry for Cooperation, and the US National Institutes of Health. The Medicines for Malaria Venture arose from discussions between the World Health Organization and the International Federation of Pharmaceutical Manufacturers Associations. Early partners in these exploratory discussions were the Global Forum for Health Research, the Rockefeller Foundation, the World Bank, the Swiss Agency for Development and Cooperation, the Association of the British Pharmaceutical Industry, and the Wellcome Trust.
7. Now called Clitophilus scyphoides.
8. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Reviews Drug Discovery 6, 29-40 (January 2007). Made available here by permission of Nature Reviews Drug Discovery.
