© 2003 Nature PublishingGroup PERSPECTIVES organisms become widespread. The number of new antibiotics that are needed to treat the same bacterial infection also increases reciprocally. For example, in the 1940s, staphylococcal infections were treated with first-generation penicillins.Within a year, resistance had appeared in Staphylococcus aureus, and a decade later, ß-lactam resistance had spurred the development and introduction of methicillin. Methicillin-resistant S. aureus (MRSA) became so prevalent that, in 1986, vancomycin became a front-line antibiotic to treat MRSA infections. Since then, MRSA have evolved to vancomycinresistant S. aureus (VRSA), and the quinupristin/dalfopristin combination (Synercid) and then linezolid (Zyvox) were approved in the late 1990s as new therapeutic options2,3. Current molecules In 2002, the global antibiotic market was estimated at US $25 billion4 and six antibiotics each topped US $1 billion in sales3. This set of six antibiotics comprises two ß-lactams, ceftriaxone (Rocephin) and an amoxicillin/clavulanate combination (Augmentin), two MACROLIDES, azithromycin (Zithromax) and clarithromycin (Biaxin), and two fluoroquinolones, ciprofloxacin (Cipro) and levafloxacin (Levaquin). These six antibiotics reflect three structural classes, which have been the mainstay of antibiotic scaffolds for four decades. Ceftriaxone (Rocephin) is a third-generation cephalosporin and Augmentin is a combination of the ß-lactamase inhibitor clavulanate and the secondgeneration penicillin amoxicillin — reflecting the enormous effort in semi-synthetic improvements to ß-lactam natural products to combat successive waves of resistant pathogens. Analogously, zithromax and biaxin are second-generation variants of the natural product erythromycin. Third-generation macrolides, the 3-ketolides, have now been approved in Europe and are under review in the United States for clinical approval. In turn, the best-selling fluoroquinolones are second-generation…