Antibacterial target

This article summarises the general characteristics of a novel antibacterial target, peptide deformylase (PDF) and reviews the design, structure-activity relationships (SAR) and properties of known PDF inhibitors, including pre-clinical and clinical data for the most advanced members of this class. 

As an example, the bifimctional epoxy ester core (+)-2 was reacted with building blocks 3-18 to yield solution-phase library NGL127A443 containing nominally 512 substitutionally and stereochemically unique compounds (Figs. 3.3, 3.4). Of these, 82% have a molecular weight unique to 0.050 amu. This library was combined with four other 500-member libraries to form a 2500-member primary library that was screened against the important antibacterial target dihydrofolate reductase (DHFR, also known as Fol-A). 

Abergel, C., Coutard, B., Byrne, D., Chenivesse, S., Claude, J. B., Deregnaucourt, C., et al. (2003). Structural genomics of highly conserved microbial genes of unknown function in search of new antibacterial targets. /. Struct. Funct. Genomics 4,141-157. 

D. W. Green (2002). The bacterial cell wall as a source of antibacterial targets. Expert Opinion... 

J Zhang, D Christensen, JE Kranz. RNase P as a novel antibacterial target. Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Washington, DC, 1997, p 186. 

WS Faraci. Cytosolic enzymes in peptidoglycan synthesis as potential antibacterial targets. In J Sutcliffe, NH Georgopapadakou, eds. Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York Chapman Hall, 1992, pp 176-204. 

KA Bostian, MB Schmid. New antibacterial targets and new approaches for drug discovery. In WD Busse, HJ Zeiler, H Labischinski, eds. Antibacterial Therapy Achievements, Problems and Future Perspectives. Berlin Springer-Verlag, 1997. 

Penicillins have been considered for the inhibition of other bacterial serine enzymes than the DD-peptidases and /3-lactamases. For instance, bacterial signal peptidases (SPases) are essential for cell viability and therefore represent nowadays a class of novel antibacterial target <1998NAT186>. SPases are involved in protein translocation through the cytoplasmic membrane in the final step of the bacterial protein secretion pathway <1997PSC1119>. 5(S)-Stereoisomers of penems have been found to inhibit SPases <1995BML443>. The most potent inhibitors are 5/AV-tricyclic penems <2003S1732>. 

Wong KK, Pompliano DL. Peptidoglycan biosynthesis. Unexploited antibacterial targets within a familiar pathway. Adv. Exp. Med. Biol. 1998 456 197-217. 

All aspects relating to the bacterial cell wall structure have been reviewed recently. Among the topics covered are the cytoplasmic steps of peptidoglycan synthesis, Lipid II as biosynthetic intermediate and antibacterial target, PBP structure and catalysis, peptidoglycan hydrolytic remodeling, structural... 

Key Words Antibacterial drug discovery antibacterial target antimicrobial chemotherapy. 

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