Bacillus subtilis revives conventional antibiotics against Staphylococcus aureus osteomyelitis

As treatment of Staphylococcus aureus (S. aureus) osteomyelitis is often hindered by the development of antibiotic tolerance, novel antibacterial therapeutics are required. Here we found that the cell-free supernatant of Bacillus subtilis (B. subtilis CFS) killed planktonic and biofilm S. aureus, and increased S. aureus susceptibility to penicillin and gentamicin as well. Further study showed that B. subtilis CFS suppressed the expression of the genes involved in adhesive molecules (Cna and ClfA), virulence factor Hla, quorum sensing (argA, argB and RNAIII) and biofilm formation (Ica and sarA) in S. aureus. Additionally, our data showed that B. subtilis CFS changed the membrane components and increased membrane permeabilization of S. aureus. Finally, we demonstrated that B. subtilis CFS increased considerably the susceptibility of S. aureus to penicillin and effectively reduced S. aureus burdens in a mouse model of implant-associated osteomyelitis. These findings support that B. subtilis CFS may be a potential resistance-modifying agent for β-lactam antibiotics against S. aureus.