Designer drugs for discerning bugs

Abstract

Almost all antibiotics used in clinical medicine owe their origin to natural compounds. Discovery of these compounds has traditionally been driven by an outward-looking Saganesque conviction (somewhere, something incredible is waiting to be known) that broad screening of many hundreds of species of bacteria and fungi would unearth novel antimicrobials. Indisputably, this approach has yielded results. More than 200 species of free-living actinomycete bacteria have been shown to produce antimicrobial compounds. Many of these compounds have been of medical value, and their usefulness could be expanded by chemical tweaking to improve pharmacological properties. The discovery and development of antimicrobial drugs has, however, been an arduous and expensive process. For instance, the macrolide antibiotic erythromycin originates in the actinomycete Saccharopolyspora erythraea and has been derivatized by numerous pharmaceutical companies over the past 50 y to yield thousands of compounds (1); a few promising leads were then subjected to lengthy pharmacokinetics testing, toxicological studies, and clinical trials in preparation for the approval process. After finally entering the clinic, the lifespan of an antimicrobial drug might be short and risks being curtailed at any time by bacterial resistance. Such considerations have caused major drug companies to opt out of antimicrobial development (2), leaving medical science without an adequate flow of new antibiotics. The drug discovery process obviously needs streamlining but not at the expense of drug testing, safety, and approval. Two studies in PNAS (3, 4) indicate how the antimicrobial pipeline might be fed with likely drug candidates that target the bacterial ribosome.