Rational identification of new antibacterial drug targets that are essential for viability using a genomics-based approach.

In the last two decades, the search for completely novel antibacterial agents has acquired a new sense of urgency due to the remarkable rise of antibiotic resistance among key bacterial pathogens. More recently, the advent of bacterial genomics has provided investigators with the data and bioinformatic tools to rationally identify novel antibacterial targets and the genome-scaled methodologies to validate them. Only 6 years have elapsed since the publication of the first complete bacterial genome sequence, but more than 50 complete microbial genome sequences are now available. This review will discuss the advantages and limitations of the existing bacterial genome dataset for the rational identification of novel antibacterial targets. Since the ability to rapidly identify essential genes where loss of function is coincident with loss of viability is the most important task of genomics-based target validation, essentiality testing methodologies (in which molecular genetic techniques are used to determine whether or not a gene product is required for viability of the parent cell) will be surveyed and their amenability to genome-scaled analysis assessed. Finally, we will discuss the impact of bacterial genomics to date on the development of novel and effective antibiotics.