MC-02479

RWJ-54428 (also known as MC-02,479) is a new cephalosporin with promising activity against gram-positive bacteria. The pharmacodynamics (PDs) of RWJ-54428 against Staphylococcus aureus , Streptococcus pneumoniae , and Enterococcus faecalis were studied in a neutropenic mouse thigh infection model. The RWJ-54428 MICs ranged from 0.25 to 1 mg/liter. Mice with ca. 10 6 CFU/thigh at the initiation of therapy were treated intraperitoneally with RWJ-54428 at doses that ranged from 3 to 1,200 mg/kg of body weight/day (in 2, 3, 4, 6, or 12 divided doses) for 24 h. The maximal reductions in bacterial counts in thigh tissues at 24 h for the methicillin-resistant S. aureus , penicillin-resistant S. pneumoniae , and E. faecalis strains were −2.8, −3.8, and −1.7 log 10 CFU/thigh, respectively. The percentage of a 24-h dosing interval that the unbound serum RWJ-54428 concentrations exceeded the MIC ( fT>MIC ) was the pharmacokinetic (PK)-PD parameter that best described the efficacy of RWJ-54428. The fT>MIC s for a bacteriostatic effect (no net change in the numbers of CFU/thigh over 24 h) ranged from 14 to 20% for staphylococci and streptococci; for maximal reductions in the numbers of CFU/thigh, the fT>MIC s ranged from 22 to 36% for these strains. For E. faecalis , the ranges of fT>MIC s for static and maximal effects were 30 to 46% and 55 to 60%, respectively. These data show that treatment with RWJ-54428 results in marked antibacterial effects in vivo, with the PK-PD parameters for efficacy being comparable to those for the efficacy of penicillins and carbapenems active against staphylococci and pneumococci.

A novel approach (TOMOCOMD-CARDD) to computer-aided "rational" drug design is illustrated. This approach is based on the calculation of the non-stochastic and stochastic linear indices of the molecular pseudograph's atom-adjacency matrix representing molecular structures. These TOMOCOMD-CARDD descriptors are introduced for the computational (virtual) screening and "rational" selection of new lead antibacterial agents using linear discrimination analysis. The two structure-based antibacterial-activity classification models, including non-stochastic and stochastic indices, classify correctly 91.61% and 90.75%, respectively, of 1525 chemicals in training sets. These models show high Matthews correlation coefficients (MCC=0.84 and 0.82). An external validation process was carried out to assess the robustness and predictive power of the model obtained. These QSAR models permit the correct classification of 91.49% and 89.31% of 505 compounds in an external test set, yielding MCCs of 0.84 and 0.79, respectively. The TOMOCOMD-CARDD approach compares satisfactorily with respect to nine of the most useful models for antimicrobial selection reported to date. Finally, an in silico screening of 87 new chemicals reported in the anti-infective field with antibacterial activities is developed showing the ability of the TOMOCOMD-CARDD models to identify new lead antibacterial compounds.