Genomics and Antimicrobial Drug Discovery

The increasing frequency of nosocomial infections due to methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) and the fear that high-level vancomycin resistance will eventually spread to staphylococci underscore the need for vigilance in the continuing war against pathogenic microbes (18, 39). Current widely used antibiotics are targeted at a surprisingly small number of vital cellular functions: cell wall, DNA, RNA, and protein biosynthesis (Table ​(Table1),1), and instances of resistance to these antibiotics are widespread and well documented (48). Thus, there is little doubt that new antibiotics are needed to combat the growing problem of antibiotic-resistant bacteria, and targeting of new pathways will likely play an important role in discovery of these new antibiotics. In fact, a number of crucial cellular pathways, such as secretion, cell division, and many metabolic functions, remain untargeted today. In the last 3 years, high-throughput automated random genomic DNA sequencing together with robust fragment assembly tools has delivered a wealth of genomic sequence information to assist in the search for new targets. In many cases, entire biochemical pathways can be reconstructed and compared in different pathogens. The purpose of this minireview is to indicate where this information can be found, to outline some of the ways in which it can be used, and to describe new tools to take advantage of genomic sequence information in the drug discovery process. TABLE 1 Gene targets of widely used antibiotics Each potential new antibiotic must meet a number of criteria before it is approved for use, and the choice of an appropriate target is the first step in this process. It is helpful to review the utility of genomic information with regard to some of the key criteria which antimicrobial targets must meet. In general, (i) a target should provide adequate selectivity and spectrum, yielding a drug which is specific or highly selective against the microbe with respect to the human host but also active against the desired spectrum of pathogens; (ii) a target should be essential for growth or viability of the pathogen, at least essential under conditions of infection; and (iii) something about the function of the target should be known so that assays and high-throughput screens can be built. Identification of potential new targets can proceed from any one of these criteria, but ultimately all must be met by a successful target. For example, a variety of methods may be used to find genes which are essential for the survival of an organism under defined conditions or which are necessary for infectivity in an animal model. Comparative genomics may be used to identify potential targets which are shared across multiple microbial species. Several tools, primarily sequence similarity based, may be used to predict the function of most genes so that specific pathways can be targeted. As discussed below, genomic sequence information provides assistance in all of these areas: selectivity, spectrum, functionality, and essentiality (Fig. ​(Fig.1).1). FIG. 1 Schematic view of genomic tools applied to antimicrobial-drug discovery. See the text for details. G+ve and G-ve, gram positive and gram negative, respectively.