Lysosomal alkalization to potentiate eradication of intra-osteoblastic Staphylococcus aureus in the bone and joint infection setting
Résumé
OBJECTIVES: Beyond intracellular penetration, acidic lysosomal pH might affect the intracellular activity of some antimicrobials. This study evaluated the ability of lysosomotropic alkalizing agents to potentiate the antimicrobial eradication of an intra-osteoblastic Staphylococcus aureus reservoir in the setting of bone and joint infection (BJI).METHODS: MICs of 16 anti-staphylococcal molecules active against methicillin-sensitive S.aureus (MSSA) were evaluated at pH 5 and pH 7. Additionally, the lysosomal alkalizing potential (spectrofluorometry) and cytotoxicity (MTT assay) of hydroxychloroquine, amantadine and ammonium chloride were assessed. The results led to further investigation of clindamycin, cotrimoxazole, daptomycin and levofloxacin-alone or in combination with hydroxychloroquine-in an invitro model of osteoblast infection. The impact of hydroxychloroquine on autophagy was finally investigated using Western blot detection of two autophagic flux indicators, the LC3 membrane protein and the SQSTM1 cargo protein.RESULTS: Daptomycin, cotrimoxazole, clindamycin and levofloxacin alone significantly decreased the intracellular staphylococcal reservoir (5.12 log10CFU/100000cells) by 0.14 (95%CI 0.01-0.34), 0.25 (95%CI 0.12-0.43), 0.16 (95%CI 0.004-0.39) and 1.18 (95%CI 1.04-1.38) log10CFU/100000cells, respectively (p
Mots clés
ANTI-BACTERIAL AGENTS
ANTIMICROBIAL
BONE AND JOINT INFECTION
BONE DISEASES, INFECTIOUS
CLINDAMYCIN
DAPTOMYCIN
HUMANS
HYDROXYCHLOROQUINE
INTRACELLULAR ACTIVITY
JOINT DISEASES
LEVOFLOXACIN
LYSOSOMAL ALKALIZATION
LYSOSOMES
MICROBIAL SENSITIVITY TESTS
SEQUESTOSOME-1 PROTEIN
STAPHYLOCOCCAL INFECTIONS
STAPHYLOCOCCUS AUREUS
TRIMETHOPRIM, SULFAMETHOXAZOLE DRUG COMBINATION
Domaines
Maladies infectieuses| Origine | Fichiers produits par l'(les) auteur(s) |
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