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Background  Chronic infection by  Staphylococcus aureus  drives pathogenesis in important clinical settings, such as recurrent pulmonary infection in cystic fibrosis and relapsing infection in osteomyelitis. Treatment options for intracellular  S. aureus  infection are limited. Rifampin, a lipophilic antibiotic, readily penetrates host cell membranes, yet monotherapy is associated with rapid antibiotic resistance and development of severe adverse events. Antibiotic cotreatment can reduce this progression, yet efficacy diminishes as antibiotic resistance develops. ML141 and simvastatin inhibit  S. aureus  invasion through host-directed rather than bactericidal mechanisms.    Objective  To determine whether cotreatment of ML141 or of simvastatin with rifampin would enhance rifampin efficacy.    Methods  Assays to assess host cell invasion, host cell viability, host cell membrane permeability, and bactericidal activity were performed using the human embryonic kidney (HEK) 293-A cell line infected with  S. aureus  (29213) and treated with vehicle control, simvastatin, ML141, rifampin, or cotreatment of simvastatin or ML141 with rifampin.    Results  We found cotreatment of ML141 with rifampin reduced intracellular infection nearly 85% when compared to the no treatment control. This decrease more than doubled the average 40% reduction in response to rifampin monotherapy. In contrast, cotreatment of simvastatin with rifampin failed to improve rifampin efficacy. Also, in contrast to ML141, simvastatin increased propidium iodide (PI) positive cells, from an average of 10% in control HEK 293-A cells to nearly 20% in simvastatin-treated cells, indicating an increase in host cell membrane permeability. The simvastatin-induced increase was reversed to control levels by cotreatment of simvastatin with rifampin.    Conclusion  Taken together, rifampin efficacy is increased through host-directed inhibition of  S. aureus  invasion by ML141, while efficacy is not increased by simvastatin. Considerations regarding novel therapeutic approaches may be dependent on underlying differences in pharmacology.

peerj

Differential effects of cotreatment of the antibiotic rifampin with host-directed therapeutics in reducing intracellular Staphylococcus aureus infection