A perspective on the next generation of antibacterial agents derived by manipulation of natural products.

Natural products have been a major source of anti-infective drugs for many decades. With urgent need for new antibacterial agents to combat drug-resistant bacteria, the investigation of both new and existing classes of natural products has once again become an important focus. In this review, we highlight how a medicinal chemistry/semi-synthetic approach to natural product manipulation continues to offer a valuable strategy to overcome limitations in current therapy. Approaches to address toxicity and to improve the solubility, bioavailability and the spectrum of activity are demonstrated. Examples are drawn from aminoglycosides, glycopeptides, tetracyclines, macrolides, thiazolyl peptides, pleuromutilins and polymyxins and are taken from the current literature, patents and abstracts of symposia. In many cases, this approach has led to drug candidates currently in late stages of clinical development.