title: Bactericidal activity of ACH-702 against nondividing and biofilm Staphylococci.
abstract: Many bacterial infections involve slow or nondividing bacterial growth states and localized high cell densities. Antibiotics with demonstrated bactericidal activity rarely remain bactericidal at therapeutic concentrations under these conditions. The isothiazoloquinolone (ITQ) ACH-702 is a potent, bactericidal compound with activity against many antibiotic-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We evaluated its bactericidal activity under conditions where bacterial cells were not dividing and/or had slowed their growth. Against S. aureus cultures in stationary phase, ACH-702 showed concentration-dependent bactericidal activity and achieved a 3-log-unit reduction in viable cell counts within 6 h of treatment at ≥ 16× MIC values; in comparison, the bactericidal quinolone moxifloxacin and the additional comparator compounds vancomycin, linezolid, and rifampin at 16× to 32× MICs showed little or no bactericidal activity against stationary-phase cells. ACH-702 at 32× MIC retained bactericidal activity against stationary-phase S. aureus across a range of inoculum densities. ACH-702 did not kill cold-arrested cells yet remained bactericidal against cells arrested by protein synthesis inhibitors, suggesting that its bactericidal activity against nondividing cells requires active metabolism but not de novo protein synthesis. ACH-702 also showed a degree of bactericidal activity at 16× MIC against S. epidermidis biofilm cells that was superior to that of moxifloxacin, rifampin, and vancomycin. The bactericidal activity of ACH-702 against stationary-phase staphylococci and biofilms suggests potential clinical utility in infections containing cells in these physiological states.
authors.affiliation: Achillion Pharmaceuticals, New Haven, Connecticut, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Podos
authors.forename: Jane A
authors.initials: JA
authors.lastname: Thanassi
authors.forename: Melissa
authors.initials: M
authors.lastname: Leggio
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pucci
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D024841:Fluoroquinolones; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D000077266:Moxifloxacin; D023303:Oxazolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D013210:Staphylococcus / Q000187:drug effects*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014640:Vancomycin / Q000494:pharmacology
chemical_list: C550937:ACH 702; D000081:Acetamides; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D023303:Oxazolidinones; D011804:Quinolines; D015363:Quinolones; D013844:Thiazoles; D014640:Vancomycin; D000069349:Linezolid; D000077266:Moxifloxacin; D012293:Rifampin