1. Int J Antimicrob Agents. 2020 Feb;55(2):105848. doi:
10.1016/j.ijantimicag.2019.11.005. Epub 2019 Nov 23.

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.

Peyrusson F(1), Van Wessem A(1), Dieppois G(2), Van Bambeke F(1), Tulkens PM(3).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain (UCLouvain), avenue E. Mounier 73 Bte B1.73.05, 
B-1200 Bruxelles, Belgium.
(2)Debiopharm International SA, Chemin Messidor 5, CH-1006 Lausanne, Switzerland.
(3)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain (UCLouvain), avenue E. Mounier 73 Bte B1.73.05, 
B-1200 Bruxelles, Belgium. Electronic address: tulkens@facm.ucl.ac.be.

Antibiotics with new modes of action that are active against intracellular forms 
of Staphylococcus aureus are sorely needed to fight recalcitrant infections
caused by this bacterium. Afabicin desphosphono (Debio 1452, the active form of
afabicin [Debio 1450]) is an inhibitor of FabI enoyl-Acyl carrier protein
reductase and has specific and extremely potent activity against Staphylococci,
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). Afabicin desphosphono caused a maximum cfu decrease of about 2.5
log10 after incubation in broth for 30 h, including against strains resistant to 
vancomycin, daptomycin, and/or linezolid. Using a pharmacodynamic model of
infected THP-1 monocytes (30 h 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 fully active against strains resistant to
these comparators.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ijantimicag.2019.11.005 
PMID: 31770623

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