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.