Achillion Pharmaceuticals, New Haven, CT 06511.
ACH-702, a novel isothiazoloquinolone, was assessed for antibacterial activity against a panel of gram-positive and gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant gram-positive strains including methicillin-resistant Staphylococcus aureus (MRSA). For gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria sp., but was less active against members of the Enterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well as Legionella pneumophila and Mycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays and postantibiotic effects (PAEs) >1 h were evident in both laboratory and clinical strains of staphylococci at 10x MIC, similar in most cases to those observed for moxifloxacin at the same MIC multiple. In vivo efficacy was demonstrated against S. aureus in murine sepsis and thigh infection models with decreases in CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism-of-action include: low MIC values (=0.25 µg/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs =0.5 µg/ml) against staphylococcal strains with two mutations in both gyrA and grlA, and low frequencies for selection of higher-level resistance (<10(-10)). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates.
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