DOI: 10.1126/science.1176667 , 1089 (2009); 325Science et al.Michael A. Fischbach,Antibiotics for Emerging Pathogens www.sciencemag.org (this information is current as of September 15, 2009 ):The following resources related to this article are available online at http://www.sciencemag.org/cgi/content/full/325/5944/1089version of this article at: including high-resolution figures, can be found in the onlineUpdated information and services, http://www.sciencemag.org/cgi/content/full/325/5944/1089#otherarticles, 20 of which can be accessed for free: cites 50 articlesThis article http://www.sciencemag.org/cgi/collection/chemistryChemistry : subject collectionsThis article appears in the following http://www.sciencemag.org/about/permissions.dtl in whole or in part can be found at: this articlepermission to reproduce of this article or about obtaining reprintsInformation about obtaining registered trademark of AAAS. is aScience2009 by the American Association for the Advancement of Science; all rights reserved. The title CopyrightAmerican Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by theScience on September 15, 2009 www.sciencemag.orgDownloaded fromAntibiotics for Emerging PathogensMichael A. Fischbach1and Christopher T. Walsh2Antibiotic-resistant strains of pathogenic bacteria are increasingly prevalent in hospitalsand the community. New antibiotics are needed to combat these bacterial pathogens, but progressin developing them has been slow. Historically, most antibiotics have come from a small setof molecular scaffolds whose functional lifetimes have been extended by generations of synthetictailoring. The emergence of multidrug resistance among the latest generation of pathogenssuggests that the discovery of new scaffolds should be a priority. Promising approaches to scaffolddiscovery are emerging; they include mining underexplored microbial niches for natural products,designing screens that avoid rediscovering old scaffolds, and repurposing libraries of syntheticmolecules for use as antibiotics.There is a perpetual need for new anti-biotics: Whereas most drugs will be just aseffective in the future as they are today, theinevitable rise of resistance will erode the utilityof today’s antibioti cs (1). Two factors exacerbatethis supply problem by creating unique disincen-tives for antibiotic development (2). First, anti-biotics are used in smaller quantities than otherdrugs. Prescriptions for chronic illnesses can lastyears or decades, whereas a standard course ofantibiotics lasts only weeks; therefore, antibioticsyield lower revenues than most drugs. Second,whereas most newly approved drugs can be pre-scribed to all who would benefit, the use of anewly approved antibiotic may be restricted tothe treatment of serious bacterial infections. Theresult is a quandary: Resistance is on the risewhile antibiotic discovery and development areon the decline (3, 4).The unfavorable economics of antibiotic de-velopment have had a chilling effect on industrialdiscovery programs, and policy-based efforts toreverse this decline deserve attention (3). This per-spective focuses on a different, yet no less formi-dable, challenge: finding new classes of antibiotics.On the face of it, antibiotic discovery wouldseem to be straightforward. The goal is to kill anorganism that is only distantly related to humans;unique, essential targets should be abundant, andnovel antibiotics with low toxicity should be easyto find. Yet, the history of antibiotic developmentsuggests otherwise. Since the early 1960s, onlyfour new classes of antibiotics have been intro-duced, and none of these has made a major impactyet; the ~$30 billion global antibiotics market isstill dominated by antibiotic classes discoveredhalf a century ago. Since then, most “new” anti-biotics have been chemically tailored derivativesof these well-worn scaffolds. In this review , weargue that the rise of resistant pathogens shouldredouble our focus on discovering not just newantibiotics, but new classes of antibiotics. We thenhighlight some promising approaches to scaffolddiscovery: mining underexplored microbial nichesfor natural products, designing screens that avoidrediscovering old scaffolds, and repurposing li-braries of synthetic molecules for use as antibiotics.A New Generation of Resistant PathogensThree classes of antibiotic-resistant pathogens areemerging as major threats to public health (Fig.1). First, methicillin-resistant Staphylococcus aureus(MRSA) is estimated to cause ~19,000 deaths peryear in the United States (5). Apart from theirhigh mortality rate, MRSA infections lead to anestimated $3 billion to $4 billion of additionalhealth care costs per year . Furthermore, the risingprevalence of MRSA increases the likelihood thatvancomyc in-res istant S. aureus (VRSA) (6)—justas deadly as MRSA but more challenging totreat—will become a new scourge in hospitals.Pathogens from the second class, multidrug-resistant (MDR) and pandrug-resistant (PDR) Gram-negative bacteria, are less prevalent than MRSA,but they pose the grave threat of infections that aretruly untreatable (7). These strains of Acinetobacterbaumannii, Escherichia coli, Klebsiella pneumoniae,and Pseudomonas aeruginosa are resistant to some(MDR) or all (PDR) of the antibiotic classes com-monly used to treat Gram-negative bacteria: penicil-lins, cephalosporins, carbapenems, monobactams,quinolones, aminoglycosides, tetracyclines, andpolymyxins (7). Prospects for finding new anti-biotics for Gram-negative pathogens are especiallypoor: Their outer membrane blocks the entry ofsome antibiotics, and efflux pumps expel manyof the remainder.The third class comprises MDR and extensivelydrug-resistant (XDR) strains of Mycobacteriumtuber culosis (MDR-TB and XDR-TB), which area rising threat in the developing world (8). MDR-TB treatment requires a 2-year course of antibioticswith serious side effects; XDR-TB is even moredifficult to cure and often fatal (9). Cases of MDR-TB and XDR-TB have been reported in the UnitedStates and other developed countries.In spite of the rise of resistant pathogens, therate of new antibiotic approvals is dropping. Wherewill new antibiotics come from? In the past, thisREVIEW1DepartmentofMolecularBiologyandCenterforComputationaland Integrative Biology, Massachusetts General Hospital, Boston,MA 02114,