Bacterial “Genes-to-Screens” in the Post-Genomic Era

Abstract

In recent years, it has become increasingly apparent that the effectiveness of our antibiotic armamentarium is becoming severely eroded by microbial resistance (1–3). The breadth of resistance mechanisms is astonishing and alarming. Genes for inactivating antibiotics on transmissible elements, antibiotic target modifications, and efflux pumps are only a few examples of a bewildering array of resistance strategies employed by microbes. At the same time, the search for novel antimicrobial agents has slowed dramatically as pharmaceutical companies turned their drug development efforts elsewhere. It is also apparent that whereas the early years of antibiotic discovery led to a number of antibiotics of differing chemical classes, these “classical” methods of antimicrobial identification yielded diminishing returns. Most of these antibiotics were derived from natural product sources, and the screens to identify their presence were relatively crude growth-inhibition assays. Although this offered advantages in terms of finding potent inhibitors that could reach their cellular targets, it ruled out moderately active compounds (that might be dramatically improved) or compounds present in lower concentrations. Indeed, it has been argued that the few soil organisms that are sources of antibiotics are overproducing mutants. Whatever the ultimate explanation may be, the fact remains that all clinically useful antibiotics are members of a very limited number of structural classes that were discovered over 30 years ago.