Oxazolidinone

Antibiotics New classes of antibacterial agents with novel mechanisms of action are urgently needed to combat the increase in multidrug resistant infections. Recent reports indicate that in 1998, at least 21% of all nosocomial enterococcal infections in US hospitals were due to vancomycin-resistant enterococci (VRE). The oxazolidinones, a new class of totally synthetic antibacterial agents, are activity against a variety of clinically impotent susceptible and resistant Gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA), VRE, and penicillin-resistant Streptococcus pneumonia (PRSP). Scientists at DuPont originally discovered this class of agents in the late 1980's. However, development of DuP-721, the drug candidate that emerged from these initial studies, was discontinued following Phase I clinical trials. Subsequently, researchers at Pharmacia and Upjohn identified two clinical candidates, eperezolid and linezolid. Linezolid is currently marketed for the treatment of multidrug resistant Gram-positive infections such as nosocomial and community-acquired pneumonia and skin infections.

Several SAR studies of the oxazolidinones have demonstrated a high tolerance for structural variation at the 4-position of the phenyl ring, while the oxazolidinone ring is essential for its activity. Based on these reports, we are planning to develop a new oxazolidinone antibacterial agent modifying the morpholine moiety of linezolid with various functional heterocycle rings.

(Written by Dr. Young-Hwan Ha / Senior Researcher)

PDF Inhibitors

Introduction : The emergence of bacterial pathogens that are resistant to multiple classes of existing antibiotics has created an urgent demand for new antibacterial agents with novel mechanisms of action. In bacteria, protein synthesis is initiated by formyl-methionyl-tRNA. As a result, all nascent polypeptides carry transiently a formylated N-terminus. Peptide deformylase (PDF) catalyzes the removal of the formyl group from those polypeptides, and subsequently methionine aminopeptidase hydrolyzes N-blocked polypeptides to produce mature proteins. Unlike the bacterial protein synthesis, cytosolic protein synthesis in mammalian cells does not involve the formyl group and PDF is apparently absent. Thus, the essential role of PDF in all bacterial protein synthesis provides a rational basis for selectivity, making it an attractive broad-spectrum antibiotic target.

Current Status : We have constructed non-peptidic benzoic acid-based small focused library as PDF inhibitors and evaluated its PDF inhibitory activity by PDF-formate dehydrogenase coupled assay. High throughput screening has been also carried out to find hits with novel scaffolds. Among benzoic acid-based focused library, a few hits are as potent as actinonin, a potent natural PDF inhibitor, in PDF inhibitory activity. We have gained some insight into the structure activity relationship of non-peptidic benzoic acid-based inhibitors. These results will be helpful in designing new non-peptidic PDF inhibitors.

(Written by Dr. Jong-Kook Lee / Senior Researcher)