Resistance to Linezolid

Abstract

The fi rst description of oxazolidinones as antibacterials was reported by researchers from the DuPont company in 1987. Compounds Dup-105 and DuP-721 (Fig. 1) were introduced as clinical candidates with good activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, in an in vivo animal effi cacy model (1). These compounds demonstrated lethal toxicity in animal models and were not further developed (2). Researchers at Pharmacia (now Pfi zer) became interested in these molecules and began a chemistry/screening effort to improve the in vitro, in vivo, and safety profi les of oxazolidinones. The DuPont group had established a structure–activity profi le for oxazolidinones (3, 4), but no information was available describing structure–toxicity relationships. Using DuP-721 as the prototype oxazolidinone, the Pharmacia group began modifying the phenyl ring, tracking the in vitro and in vivo activity of the analogs in order to select compounds that were similar to DuP-721 in potency. This effort yielded several molecules, the most exciting of which was PNU-82965 (Fig. 1) (5, 6). This compound contained an indanone ring as a replacement for the phenyl ring and acetyl moieties of Dup-721. A head-to-head comparison of Dup-721 and PNU-82965 in a 30-day rat toxicology study revealed that the latter compound was far superior in safety to Dup-721, thereby establishing the fi rst structure–toxicity relationship for oxazolidinones and paving the way for the synthesis of additional analogs that focused on suitable replacements for the phenyl and acetyl moieties of Dup-721. This effort led to the troponylphenyloxazolidinones, indolinyloxazolidinones, and the piperazinylphenyloxazolidinones subclasses (5). The poor water solubility and poor pharmacokinetic characteristics of the troponyl analogs prevented further exploration of this subclass of compounds, while indolines had a good safety profi le but reduced antibacterial activity. Fortunately, the piperazine analogs were superior in all biological activities, plus they were much easier to synthesize. Two clinical candidates emerged from the piperazine chemistry effort in the form of PNU-100592 (eperezolid) and PNU-100766 (linezolid). These two compounds (Fig. 1) were virtually identical in terms of antibacterial activity and in vivo animal effi cacy, and both were well tolerated in rat toxicology studies. Eperezolid and linezolid simultaneously entered Phase I clinical testing in late 1994 and early 1995, respectively. The superior pharmacokinetic profi le of linezolid resulted in further development, eventually gaining Food and Drug Administration (FDA) approval in March 2000.