F1-2023. Bactericidal Activity of ACH-702 against Non-dividing Staphylococci
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.
Jane Thanassi1, Jijun Cheng, PhD1, Michael Pucci, PhD2, Milind Deshpande, PhD1, Steven Podos, PhD2 and  S. D. Podos,
Achillion Pharmaceuticals Role(s): Employee, Received: Salary., (1)Achillion Pharmaceuticals, (2)Achillion Pharmaceuticals, New Haven, CT

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