In Vitro and In Vivo Antibacterial Activities of Heteroaryl Isothiazolones against Resistant Gram-Positive Pathogens

Abstract

The activities of several tricyclic heteroaryl isothiazolones (HITZs) against an assortment of gram-positive and gram-negative clinical isolates were assessed. These compounds target bacterial DNA replication and were found to possess broad-spectrum activities especially against gram-positive strains, including antibioticresistant staphylococci and streptococci. These included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-nonsusceptible staphylococci, and quinolone-resistant strains. The HITZs were more active than the comparator antimicrobials in most cases. For gram-negative bacteria, the tested compounds were less active against members of the family Enterobacteriaceae but showed exceptional potencies against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. Good activity against several anaerobes, as well as Legionella pneumophila and Mycoplasma pneumoniae, was also observed. Excellent bactericidal activity against staphylococci was observed in time-kill assays, with an approximately 3-log drop in the numbers of CFU/ml occurring after 4 h of exposure to compound. Postantibiotic effects (PAEs) of 2.0 and 1.7 h for methicillin-susceptible S. aureus and MRSA strains, respectively, were observed, and these were similar to those seen with moxifloxacin at 10؋ MIC. In vivo efficacy was demonstrated in murine infections by using sepsis and thigh infection models. The 50% protective doses were <1 mg/kg of body weight against S. aureus in the sepsis model, while decreases in the numbers of CFU per thigh equal to or greater than those detected in animals treated with a standard dose of vancomycin were seen in the animals with thigh infections. Pharmacokinetic analyses of treated mice indicated exposures similar to those to ciprofloxacin at equivalent dose levels. These promising initial data suggest further study on the use of the HITZs as antibacterial agents.

Investigational Antimicrobial Agents of 2013

“…ACH-702 (Achillion Pharmaceuticals) (Fig. 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).…”

Challenges of Antibacterial Discovery

“…Members of Achillion's heteroaryl isothiazolone (HITZ) series (69) have a broad Gram-positive spectrum, with activity against H. influenzae, Moraxella catarrhalis, and Neisseria spp. (304), very low resistance potential, activity against FQ-resistant strains (69), and in vivo efficacy in S. aureus septicemia and thigh abscess models in the mouse (304). Achillion's apparent current lead compound, ACH-702 (Fig.…”

Bactericidal Activity of ACH-702 against Nondividing and Biofilm Staphylococci

“…Consequently, despite a shared molecular poison mechanism of enzyme complex formation with DNA and compound, only those quinolone compounds that preferentially target DNA gyrase over topoisomerase IV effect an immediate blockage in DNA synthesis (22). While most quinolones primarily target topoisomerase IV in S. aureus (1), we have previously reported microbiological and biochemical evidence that the ITQ compounds, including ACH-702, potently target both DNA gyrase and topoisomerase IV (4,36,37,41). We hypothesize that this superior potency of ACH-702 against the DNA gyrase target underlies its improved bactericidal potency against nondividing staphylococci (Fig.…”

“…S. aureus time-kill studies were generally done as previously described (36). Briefly, for exponential-phase S. aureus, overnight cultures of ATCC 29213, ATCC 33591, and BK2384 were diluted into fresh medium and grown with shaking at 37°C for 1 h before treatment at approximately 10 7 CFU/ml with ACH-702 or other antibacterial agents.…”

“…We previously described a class of compounds designated isothiazoloquinolones (ITQs) that possess potent activities against Gram-positive pathogens with a bactericidal mode of action (36). In S. aureus, ITQs and quinolones share the same targets, DNA gyrase and topoisomerase IV (4).…”