The Role of Genomics in Antibacterial Target Discovery

Abstract

Complete DNA sequence information has now been obtained for several prokaryotic genomes, defining the entire genetic complement of these organisms. The collection of genomic data has provided new insights into the molecular architecture of bacterial cells, revealing the basic genetic and metabolic structures that support viability of the organisms. Genomic information has also revealed new avenues for inhibition of bacterial growth and viability, expanding the number of possible drug targets for antibiotic discovery. This review examines how genomic sciences and experimental tools are applied to antibacterial target discovery, the necessary first step in the development of new antibiotic classes. Significant advances have been realized in the development of functional genomic, comparative genomic, and proteomic methods for the analysis of completed genomes. The combination of these methods can be used to systematically parse the genome and identify targets worthy of inhibitor screens. Two basic categories of targets emerge from this exercise, comprising in vitro essential targets required for bacterial viability on synthetic media and in vivo essential targets required to establish and maintain infection within a host organism. Current use of genomic information is focused primarily on a definition of all in vitro essential targets that satisfy criteria of selectivity, spectrum, and novelty. As the genomes of additional bacterial pathogens are solved, it will be possible to select in vivo essential targets common to groups of select pathogens (e.g., bacterial agents of community acquired pneumonia) or even pathogen-specific targets. Consideration of host-pathogen interactions, defined at the level of gene expression for each organism, might provide novel therapeutic options in the future.

Comparative genomics: methods and applications

“…More sophisticated tasks include the description of a minimal genome for free-living organisms Hutchison III et al 1999;Makarova and Koonin 2003), the comparison of non-redundant proteomes of eukaryotes , structural and functional genome annotation (Dermitzakis et al 2002;Brachat et al 2003;Kessler et al 2003;Werner 2003a), and the detection of selection (Mouse Genome Sequencing Consortium 2002;Schlötterer 2003). Of particular medical interest is the comparison of bacterial pathogens (Cole 1998;Field et al 1999;Brosch et al 2001;Buysse 2001;Fitzgerald and Musser 2001;Andersson et al 2002;Schoolnik 2002), medical diagnosis (Willey et al 2002;Zhou et al 2002), and the mapping of disease genes (Horikawa et al 2000). All these tasks rely on comparative sequence data, which are currently being generated at an unprecedented rate.…”

Large-Scale Identification of Genes Required for Full Virulence ofStaphylococcus aureus

“…These functions must certainly be important in permitting S. aureus to survive and replicate in the variety of distinct in vivo environments encountered by this pathogen (45). The development of new molecular and genetic methods for the analysis of bacterial pathogenesis has enabled comprehensive screening of bacterial genomes for virulence genes in animal hosts (4). Among these methods are promoter trap strat-egies, such as in vivo expression technology, a method that selects for genes specifically expressed during infection (40), and differential fluorescence induction, which monitors expression of the green fluorescent protein (gfp) reporter gene as a measure of promoter activity in vivo (55).…”

Community-Acquired Pneumonia and Outcome: The Importance of Genetics

“…However, the real key is to identify in vivo targets required to establish and maintain infection within the host organism. Consideration of host-pathogen interactions, defined at the level of gene expression for each will be essential [49].…”

“…The elderly, in particular, who may present with fewer symptoms or vague complaints [50,51], may benefit greatly from genetic analysis. Furthermore, consideration of host-pathogen interactions, defined at both the DNA level and the level of gene expression (RNA) might provide not only novel therapeutic options in the future [49], but much needed predictive tools.…”