Prospects and challenges of developing new agents for tough Gram-negatives.

Historically, the medical profession has been successful in treating most bacterial infections in humans with synthetic second- and third-generation antibiotics. Recently, the prospects for continued success have dimmed with the increase in multidrug-resistant stains of bacteria. Infections caused by the Gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter spp. in particular have increased in frequency and severity, and become progressively more difficult to treat. Contributors to disease severity include chronic infections due to mutator strains, persister cells and biofilms. The worst-case scenario of infections susceptible only to toxic polymixins is now a reality. The need to address the treatment of multidrug-resistant pathogens with innovative combination approaches and/or novel antibacterial agents is occurring in the context of reduced investment in antimicrobial drug discovery by the pharmaceutical industry.