100,000 people to 36 per 100,000 people, a reduction by a factor of more than 20 and a testament in part to the efficacy of antibiotics (Armstrong et al. 1999). However, from 1980 to 2000, that rate doubled, largely because of HIV but also due to the spread of drug-resistant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, multiple-drug-resistant gram-negative bacteria, and multiple-drug-resistant tuberculosis (Cohen 2000). While the rise in mortality is due partly to infection in more seriously ill or immunocompromised patients, there is no doubting the need for new strategies and new molecules to treat pathogens that are resistant to nearly the full array of contemporary antibiotics. We are at a critical point, not seen since the pre-antibiotic era, at which infections caused by some bacterial pathogens are untreatable.

A second indication of the need for novel antibacterial therapeutics is the almost 40-year innovation gap between introductions of new molecular classes of antibiotics: fluoroquinolones in 1962 and the oxazolidinone linezolid in 2000 (Walsh 2003a,b). A third indication is the recent trend by several large pharmaceutical companies to leave the antibacterial and antifungal therapeutic arenas, suggesting a future decrease in scientific expertise in antibacterial-drug discovery and development skills (Projan 2003; Shlaes 2003). A technology gap is developing and widening, as research on and development of new antimicrobial agents are being de-emphasized or abandoned by many pharmaceutical companies.

Treatment of microbial infections—bacterial, fungal, and viral—selects for the emergence of resistant organisms that may be rare in the initial population but become increasingly prevalent under selective drug pressure. In fact, the presence of an antibiotic can accelerate mutation and recombination in bacterial populations and contribute directly to its own obsolescence (Cirz et al. 2005). This is in addition to resistance that may develop outside of the clinical setting; for example, resistance to penicillin had been documented even before its first widespread clinical use (Abraham and Chain 1988). Resistance is prevalent, heritable, and ancient.

The need for new generations of anti-infective agents, and in particular new antibacterial agents, is constant, as the emergence of resistance is largely a question of when and not if. Medicinal chemists have been highly successful over the last 50 years in reshaping the scaffolds of earlier antibiotics, both natural and synthetic; for example, current antibiotics include the fourth generation of beta lactams and the third generation of



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