The Targets of Currently Used Antibacterial Agents: Lessons for Drug Discovery
Pp. 62-96 (35)
Roland P. Lange, Hans H. Locher, Pierre C. Wyss and Rudolf L. Then
Based on the mode of action of antibacterial drugs currently used,
targets can be defined as distinct cellular constituents such as enzymes, enzyme
substrates, RNA, DNA, and membranes which exhibit very specific binding
sites at the surface of these components or at the interface of macromolecular
complexes assembled in the cell. Intriguingly, growth inhibition or even complete
loss of bacterial viability is often the result of a cascade of events elicited upon
treatment with an antibacterial agent. In addition, their mode of action frequently
involves more than one single target.
A comprehensive description of the targets exploited so far by commercialized
antibacterial agents, including anti-mycobacterial agents, is given. The number of
targets exploited so far by commercial antibacterial agents is estimated to be about
40. The most important biosynthetic pathways and cellular structures affected by
antibacterial drugs are the cell wall biosynthesis, protein biosynthesis, DNA per se,
replication, RNA per se, transcription and the folate biosynthetic pathway.
The disillusionment with the genomics driven antibacterial drug discovery is a
result of the restrictive definition of targets as products of essential and conserved
genes. Emphasis is made to not only focus on proteins as potential drug targets,
but increase efforts and devise screening technologies to discover new agents interacting
with different RNA species, DNA, new protein families or macromolecular
complexes of these constituents.
Antibiotic, antibacterial agents, drug design, drug discovery, drug target, target.
Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123 Allschwil, Switzerland.