Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: In many clinical bacterial infections, the causative pathogens are often found in environments that are not conducive for optimal growth. Non-dividing bacterial cells are killed less well by most currently used antibacterial agents. The isothiazoloquinolone, ACH-702, has shown rapid bactericidal activity against exponential phase bacterial cultures. The purpose of this work was to examine the bactericidal activity of ACH-702 against non-dividing staphylococci. Methods: Bactericidal activity against both exponential- and stationary-phase staphylococci was determined in Mueller-Hinton (MH) broth. Exponential cells were growth arrested by nutrient depletion, antibiotic exposure, or environmental treatment (cold temperature) prior to addition of ACH-702. Cell viability was measured by dilution and plating onto MH agar plates. Results: ACH-702 retained dose-dependent bactericidal activity against non-dividing staphylococci with a dose response observed up to 32× MIC. S. aureus ATCC 29213 stationary-phase cells showed a 3-log reduction in viability within 2 hours at 20× MIC and cells that were growth-arrested by protein synthesis inhibitors were similarly susceptible as well. This was in contrast to quinolones and other antibiotic comparators that showed little or no killing of non-dividing cells. Bactericidal activity was not observed against staphylococci whose growth was arrested by cold temperature. ACH-702 also demonstrated rapid bactericidal activity against staphylococcal biofilms in contrast to comparator compounds. Conclusion: ACH-702 was bactericidal against non-dividing staphylococcal cells whose growth was stopped by either nutrient depletion or protein synthesis inhibition. Because few other antibiotics possess this property, further investigation of this activity is warranted.