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

Abstract

ACH-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-resistant Staphylococcus aureus (MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and a 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) 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 vivo efficacy was demonstrated against S. aureus with 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 g/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of <0.5 g/ml) against staphylococcal strains with two mutations in both gyrA and grlA, 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.

Investigational Antimicrobial Agents of 2013

“…Reduced antibacterial activity was reported for Gram-negative bacteria, with the exception of the respiratory Gram-negative pathogens. 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 for the vancomycin comparator (46). Rapid metabolism of the parent compound via extensive glucuronidation precluded systemic administration, and ACH-702 was recently licensed to Ora Inc. for use in ophthalmic infections (M. Pucci, unpublished data; www .achillion.com).…”

“…The isothiazoloquinolones possess broad-spectrum antibacterial activity against important human clinical isolates, including fluoroquinolone-resistant strains, especially the Gram-positive staphylococci, S. pneumoniae, and enterococci. Against recent MRSA clinical isolates, ACH-702 exhibited an MIC 90 of 0.25 g/ml, including for quinolone-resistant isolates (46). Reduced antibacterial activity was reported for Gram-negative bacteria, with the exception of the respiratory Gram-negative pathogens.…”

“…2, compound 10) is an isothiazoloquinolone that has structural similarities to quinolones but differs due to the presence of an isothiazolone ring (44,45). Biochemical analyses indicated potent dual inhibition of the two antibacterial target enzymes, DNA gyrase and topoisomerase IV, with IC 50 s of Յ1 M for staphylococcal enzymes (46). The isothiazoloquinolones possess broad-spectrum antibacterial activity against important human clinical isolates, including fluoroquinolone-resistant strains, especially the Gram-positive staphylococci, S. pneumoniae, and enterococci.…”

Anti-methicillin Resistant Staphylococcus aureus Compound Isolation from Halophilic Bacillus amyloliquefaciens MHB1 and Determination of Its Mode of Action Using Electron Microscope and Flow Cytometry Analysis

“…Time-kill studies were done as described previously [21,22]. The 29 and 49 MIC of purified compound was added separately to the MRSA culture density of 10 7 CFU/mL and incubated at 37°C.…”

New perspectives on antibacterial drug research

“…One of them, ACH-702 (isothiazoloquinolone, Achillion Pharmaceuticals) displayed potent activity against antibiotic-resistant Gram-positive bacteria (including MRSA) in vitro and in vivo. Furthermore, it is also active against some Gram-negative bacteria (H. influenzae, Moraxella catarrhalis, and a Neisseria spp., with minor activity against Enterobacteriaceae) [54]. NXL101 is another dual inhibitor of the essential bacterial DNA replication enzymes DNA gyrase and topoisomerase IV (Novexel).…”