THERAPEUTIC STRATEGIES DRUGDISCOVERY T ODA Y Finding the gems using genomic discovery: antibacterial drug discovery strategies – the successes and the challenges Pan F. Chan, David J. Holmes, David J. Payne * Department of Microbiology, Microbial, Musculoskeletal and Proliferative Diseases, Center of Excellence in Drug Discovery, Anti-infectives Research (UP1345), GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA Since the first bacterial genome was sequenced (1995) many companies have invested in a variety of antibiotic discovery strategies but few novel-acting antibacterial agents have reached human trials. This is not through lack of trying, as from literature reports alone >125 published studies on high-throughput screens of >60 different novel targets (from 34 companies) have been identified. Post-genomics should be a new golden era of antibiotics but there are substantial challenges of deli- vering much needed, novel-acting antibacterials that will be discussed. Section Editor: Gary Woodnutt – Diversa Corp., San Diego, CA, USA The explosion in the bacterial genomics area in the past decade has been remarkable, but there appears to have been little reward for all of this effort as judged by the relative lack of new antibacterial agents entering development. Chan et al. review these developments and suggest that, as far as target identification is concerned, the use of genomics has provided us with a wealth of potentially attractive opportunities, and failure to consolidate on these reflect on other deficits/difficulties in the antibacterial drug discovery process. Furthermore, the knowledge gained during this period has allowed considerable advances in genetic tools that can assist in tracking structure–activity relationships in the whole cell, and should enable the dissection of compound mode of action. In addition, these advances have been pivotal in understanding why certain promising candidates are less viable. Thus, the bacterial genomics era is far from being over and might actually have just begun to be applied appropriately. Introduction In the past 20 years, only two completely novel classes of antibiotics have reached the market to combat the clinical threat of multidrug-resistant bacteria (Infectious Disease Society of America, http://www.idsociety.org/Template. cfm?Section=AntimicrobialsTemplate=/ContentManagement/ ContentDisplay.cfmContentID=9718). Furthermore, there is apparently only one novel-acting, systemic agent in the antibiotic development pipeline [1]. Despite the medical need for new antibiotics [2] there has been a trend for some large pharmaceutical companies to downsize or abandon their antibacterial drug discovery efforts [3]. Reasons for this withdrawal are complex and multi-factorial but one very significant factor is that in retrospect, it is significantly more challenging to deliver novel classes of antibiotics than was predicted nine years ago when the first bacterial genome was completed. In this review, we discuss three strategies for finding new antibiotics – (i) target-based screening (ii) anti- bacterial whole-cell screening and (iii) structural genomics – and examine how genomics enable or facilitate each of these strategies. In addition, we discuss the significant challenges that compromise the success of each approach. Drug Discovery Today: Therapeutic Strategies Vol. 1, No. 4 2004 Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA Infectious diseases *Corresponding author. (D.J. Payne) david_j_payne@gsk.com 1740-6773/$ ß 2004 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2004.11.003 www.drugdiscoverytoday.com 519