Oxazolidinones possessing a C-5 carboxamide functionality (reverse amides) represent a new series of compounds that block bacterial protein synthesis. These reverse amides also exhibited less potency against monoamine oxidase (MAO) enzymes and thus possess less potential for the side effects associated with MAO inhibition. The title compound (14) showed reduced in vivo myelotoxicity compared to linezolid in a 14-day safety study in rats, potent in vivo efficacy in murine systemic infection models, and excellent pharmacokinetic properties.

The present study investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationships of a prototype biotin carboxylase (BC) inhibitor, PD-0162819, against Haemophilus influenzae 3113 in static concentration time-kill (SCTK) and onecompartment chemostat in vitro infection models. H. influenzae 3113 was exposed to PD-0162819 concentrations of 0.5 to 16؋ the MIC (MIC ‫؍‬ 0.125 g/ml) and area-under-the-curve (AUC)/MIC ratios of 1 to 1,100 in SCTK and chemostat experiments, respectively. Serial samples were collected over 24 h. For efficacy driver analysis, a sigmoid maximum-effect (E max ) model was fitted to the relationship between bacterial density changes over 24 h and corresponding PK/PD indices. A semimechanistic PK/PD model describing the time course of bacterial growth and death was developed. The AUC/MIC ratio best explained efficacy (r 2 ‫؍‬ 0.95) compared to the peak drug concentration (C max )/MIC ratio (r 2 ‫؍‬ 0.76) and time above the MIC (T>MIC) (r 2 ‫؍‬ 0.88). Static effects and 99.9% killing were achieved at AUC/MIC values of 500 and 600, respectively. For time course analysis, the net bacterial growth rate constant, maximum bacterial density, and maximum kill rate constant were similar in SCTK and chemostat studies, but PD-0162819 was more potent in SCTK than in the chemostat (50% effective concentration [EC 50 ] ‫؍‬ 0.046 versus 0.34 g/ml). In conclusion, basic PK/PD relationships for PD-0162819 were established using in vitro dynamic systems. Although the bacterial growth parameters and maximum drug effects were similar in SCTK and the chemostat system, PD-0162819 appeared to be more potent in SCTK, illustrating the importance of understanding the differences in preclinical models. Additional studies are needed to determine the in vivo relevance of these results. Steadily increasing bacterial resistance to existing antibiotics continues to be a major public health concern (3, 8). Because most new antibacterial agents represent chemical modifications of existing chemical classes of antibacterial agents (5), it is suspected that the limited options of chemically distinct antibiotics have led to extensive drug resistance among bacterial pathogens. Therefore, it is of the utmost importance to identify novel, safe, and effective antibacterial agents that work through unique antibacterial biological mechanisms. The discovery of a new chemical class of antibacterial compounds, the pyridopyrimidines, targeting bacterial biotin carboxylase (BC), was recently reported (14, 15) and offers the potential that this novel chemical class, targeting a unique antibacterial mechanism, can be developed into drugs effective against multidrug-resistant bacteria.Compared to the development of drugs from an existing chemical class, the discovery of a novel class of compounds presents extra challenges (1, 5). The translation of pharmacokinetic/ pharmacodynamic (PK/PD) relationships between animal infection models and human patients has been well established for several existing chemical classes across a variety of in...