In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens

Author:

Pucci Michael J.,Podos Steven D.,Thanassi Jane A.,Leggio Melissa J.,Bradbury Barton J.,Deshpande Milind

Abstract

ABSTRACTACH-702, a novel isothiazoloquinolone (ITQ), 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-resistantStaphylococcus aureus(MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency againstHaemophilus influenzae,Moraxella catarrhalis, and aNeisseriasp. but was less active against members of theEnterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well asLegionella pneumophilaandMycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10× MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple.In vivoefficacy was demonstrated againstS. aureuswith murine sepsis and thigh infection models, with decreases in the number of 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 the following: low MIC values (≤0.25 μg/ml) against staphylococcal strains with single mutations in bothgyrAandgrlA(parC), retention of good antibacterial activity (MICs of ≤0.5 μg/ml) against staphylococcal strains with two mutations in bothgyrAandgrlA, and low frequencies for the selection of higher-level resistance (<10−10). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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