The Present

The deciphering of the complete genome of Haemophilus influenzae in 1995 [11] heralded a flood of unprecedented prokaryotic sequence information and triggered a paradigm shift in antibacterial drug discovery. It therefore seems appropriate to define this event as the starting point of the "present era" of antibiotic discovery strategies. Since that time, more than 190 complete bacterial genomic sequences have become available. That large collection of fully sequenced bacterial genomes includes those of important pathogens such as H. influenzae, S. aureus, Enterococcus faecium, Enterococcus faecalis, S. pneumoniae, P. aeruginosa, M. tuberculosis, and Escherichia coli, which are in the focus of antibacterial drug discovery today ( This development not only allowed analysis and comparison the inherently static genome of various important pathogens, but also paved the way for the introduction of genome-wide gene expression technologies such as transcriptome and proteome analysis (for review, see, e.g., Refs. [12-15]). We will discuss the importance of that progress for drug discovery in detail in Section 23.3. Suffice it to say here that this development really fuelled the hope that the urgently needed novel antibiotics could now be discovered and developed at an unprecedented pace. In fact, those technologies helped dramatically in the selection of novel antibacterial targets, in validating their importance for bacterial survival and pathogenesis, and in rapid determination of the molecular mode of action of novel lead structures in vitro and in vivo. In addition, other, unrelated technologies added to this belief, most prominently the development of high-throughput robotic screening, combinatorial and parallel synthesis methods, and the development of highly predictive animal models for all important antibacterial indications. Today, pharmaceutical companies are able to screen more than a million compounds against a specific target in biochemical or cellular test systems based on 1536 well plates in less than a week.

However, a look at the number and nature of novel antibiotics in clinical development (i.e., those that could reach the market by 2010) appears to contradict the expectation of rapid antibiotic discovery and development for the near future

(Table 23.1). Firstly, if we look just at the number of compounds, only a very limited number of novel antibacterials can be expected to become clinically available in that time span. This calculation takes into account the historical probabilities of success during clinical development, which are much higher in anti-infective development than in all other indications, but nevertheless only of the order of 30% to reach the market after first dosing to humans in phase I [1, 16]. Even more revealing appears the fact that most, if not all, of those compounds are derived from existing classes (glycopeptides, quinolones, b-lactams, macrolides), and even the peptide deformylase inhibitors such as LBM415 stem from a well-known natural compound, actinonine [17], although they have been sometimes called the first compound class derived from genomics/target-driven approaches. On the other hand, the compounds listed in Table 23.1 also tell us that much progress can still be attained within existing classes [18, 19]. For example, BAL 9141, now also known as ceftobiprole, represents the most progressed of a series of novel b-lactams which, for the first time, show promising activity against MRSA [20]. Similarly, novel molecules derived from the tetracycline class such as tigecycline and the aminomethylcycline BAY 73-7388 reveal excellent broad-spectrum activity even against gram-positive pathogens which have developed resistance to tetracy-clines via various pump and ribosomal protection mechanisms, including MRSA, VRE, DRSP, and many more [21-24]. Also, for some of the quinolones, e.g., DX-619, some remarkable activity against MRSA and quinolone-resistant grampositive organisms in general has been reported [25, 26]. Finally, glycopeptides with enhanced killing activity and long-lasting human kinetics could be mentioned, which might translate into clinical advantages [20, 27]. It remains to be seen how successful those novel antibiotics derived from already marketed classes

Table 23.1 Overview of the most important novel antibiotics in clinical development.








Phase III

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