The Contribution of Genomics to the Discovery of New Antibiotics

Abstract

The emergence of common bacterial pathogens that are resistant to multiple antibiotics, coupled with the failure of traditional methods to yield new anti-infective agents, threatens current paradigms of therapeutic intervention (Omura, 1992; Shlaes et al., 1991; Tenover and Hughes, 1996). The current focus has been on improving existing antibiotic classes while little progress has been made in discovering chemically novel anti-infective agents. This unmet medical need may now be addressed if we can successfully exploit the new wealth of genomic sequence data to devise novel strategies for drug discovery (Moir et al., 1999). Whole genome comparative sequence analysis now allows the identification of genes/gene products that are common to many or all pathogenic bacteria of clinical importance. bioinformatics-based gene homology and motif analyses allow rapid phylogenetic comparisons to be made and, in addition, predict functional information critical to target selection. Putative targets can then be assessed rapidly using gene essentiality testing methods which allow analyses both in vitro and in models of the infection state. Sensitive and direct in vivo expression analyses confirm that the expression of the target gene is relevant to the establishment and maintenance of infection. Ultimately, the gene products must be screened against novel chemical libraries and natural product banks derived from a wide bio-diversity in order to identify lead compounds with potential antibiotic activities that will be developed to provide the next generation of therapeutic agents. Those companies which can adapt and implement these genomic-based technologies, derive significant competitive advantage in creating product portfolios that will address the unmet clinical need.