Cellular pharmacokinetics and intracellular activity of the bacterial fatty acid synthesis inhibitor afabicin desphosphono against different resistance phenotypes of Staphylococcus aureus in models of cultured phagocytic cells.

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Cellular pharmacokinetics and intracellular activity of the bacterial fatty acid synthesis inhibitor afabicin desphosphono against different resistance phenotypes of Staphylococcus aureus in models of cultured phagocytic cells.

Int J Antimicrob Agents. 2019 Nov 23;:

Authors: Peyrusson F, Van Wessem A, Dieppois G, Van Bambeke F, Tulkens PM

Abstract
Antibiotics with new mode of action and active against intracellular forms are sorely needed to fight against recalcitrant infections caused by Staphylococcus aureus. Afabicin desphosphono (Debio 1452, the active form of afabicin [Debio 1450]) is an inhibitor of FabI enoyl-Acyl carrier protein reductase with specific and extremely potent activity against Staphylococci species including strains resistant to current antistaphylococcal agents. Using mouse J774 macrophages and human THP-1 monocytes, we showed that afabicin desphosphono (i) accumulates rapidly in cells, reaching stable cellular to extracellular concentration ratios of about 30; (ii) is recovered entirely and free in the cell soluble fraction (no evidence of stable association with proteins or other macromolecules). In broth, afabicin desphosphono caused a maximum cfu decrease of about 2.5 log10 after 30h of incubation, including against strains resistant to vancomycin, daptomycin, and/or linezolid. Using a pharmacodynamic model of infected THP-1 monocytes (30h of incubation post-phagocytosis), we showed that afabicin desphosphono is bacteriostatic (maximum cfu decrease: 0.56 to 0.73 log10) towards all strains tested, a behaviour shared with the comparators (vancomycin, daptomycin, and linezolid) when tested against susceptible strains. We conclude that afabicin desphosphono has a similar potential as vancomycin, daptomycin or linezolid to control the intracellular growth and survival of phagocytized S. aureus and remains insensitive to the expression of resistance mechanism(s) to these comparators.

PMID: 31770623 [PubMed - as supplied by publisher]