Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus.
Trent KunkleSanofar AbdeenNilshad SalimAnne-Marie RayMckayla StevensAndrew J AmbroseJosé VictorinoYangshin ParkQuyen Q HoangEli ChapmanSteven M JohnsonPublished in: Journal of medicinal chemistry (2018)
We recently reported the identification of a GroEL/ES inhibitor (1, N-(4-(benzo[ d]thiazol-2-ylthio)-3-chlorophenyl)-3,5-dibromo-2-hydroxybenzamide) that exhibited in vitro antibacterial effects against Staphylococcus aureus comparable to vancomycin, an antibiotic of last resort. To follow up, we have synthesized 43 compound 1 analogs to determine the most effective functional groups of the scaffold for inhibiting GroEL/ES and killing bacteria. Our results identified that the benzothiazole and hydroxyl groups are important for inhibiting GroEL/ES-mediated folding functions, with the hydroxyl essential for antibacterial effects. Several analogs exhibited >50-fold selectivity indices between antibacterial efficacy and cytotoxicity to human liver and kidney cells in cell culture. We found that MRSA was not able to easily generate acute resistance to lead inhibitors in a gain-of-resistance assay and that lead inhibitors were able to permeate through established S. aureus biofilms and maintain their bactericidal effects.
Keyphrases
- staphylococcus aureus
- methicillin resistant staphylococcus aureus
- signaling pathway
- biofilm formation
- silver nanoparticles
- pseudomonas aeruginosa
- anti inflammatory
- escherichia coli
- cystic fibrosis
- high throughput
- cell proliferation
- cell death
- molecular dynamics simulations
- cell cycle arrest
- extracorporeal membrane oxygenation
- pi k akt
- aortic dissection
- tissue engineering