29 Antibacterial effects of the MEK1/2 inhibitor ATR-002 on Staphylococcus aureus

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Objectives/Goals: Pulmonary infections by Staphylococcus aureus (S. aureus) are difficult to eradicate in people with cystic fibrosis (CF, PwCF) and remain a significant disease burden. Our objective is to determine if a MEK1/2 inhibitor, ATR-002, can reduce S. aureus biofilm growth and synergize with antibiotics against multidrug-resistant strains of S. aureus. Methods/Study Population: To quantify the ability of ATR-002 to synergize with antibiotics, synergy checkerboard assays examined the effects of ATR-002 in combination with n=11 different antibiotics against the methicillin-resistant S. aureus (MRSA) strain USA300. We next quantified bacterial growth of n=6 antibiotic-resistant CF clinical isolates treated with a combinatory dose of 5 uM ATR-002 and antibiotic to confirm results from the checkerboard assay. Finally, S. aureus biofilms were established using USA300 or n=7 different CF clinical isolates in 96-well plates for 24 hours and then were treated with media, vehicle controls, or ATR-002 (5, 25, or 50 uM) for an additional 24 hours; bacterial biomass was quantified by crystal violet staining to assess the ability of ATR-002 to decrease biofilm growth. Results/Anticipated Results: Synergy checkerboard assays revealed that ATR-002 can synergize with the antibiotics gentamicin and amikacin, but had additive/indifferent effects with clindamycin, erythromycin, nafcillin, vancomycin, doxycycline, daptomycin, sulfamethoxazole-trimethoprim, linezolid, and puromycin. Additionally, two gentamicin/amikacin-resistant CF isolates were resensitized to gentamicin and amikacin with the addition of 5 uM ATR-002. However, CF isolates resistant to erythromycin, clindamycin, and nafcillin could not be resensitized to antibiotics with the addition of 5 uM ATR-002. Biofilms produced by MRSA, and n=3 out of 7 CF clinical isolates tested were significantly reduced by treatment of 50 uM ATR-002. Discussion/Significance of Impact: Our results demonstrate that ATR-002 can synergize with some antibiotics against MRSA, which is also observed in antibiotic-resistant CF S. aureus clinical isolates, and that ATR-002 can reduce established S. aureus biofilms. Future studies will explore the antibacterial effects of ATR-002 in additional clinically relevant models of infection.

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