04/18/23 ISAP - 2009 1
Is the cellular accumulation of antibiotics a predictive factor
for intracellular efficacy ?
Sandrine Lemaire
Université catholique de Louvain & Louvain Drug Research Institute
Brussels, Belgium
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Persistence and recurrence:
the case of Staphylococcus aureus …
Intracellular Staphylococcus aureus. A mechanism for the indolence of osteomyelitisEllington et al, J Bone Joint Surg (2003), 85:918-921.
Intracellular persistence of Staphylococcus aureus Small Colony Variants within keratinocytes: a cause for antibiotic treatment failure in a patient with Darier’s disease. von Eiff et al, Clin Infect Dis (2001), 32:1643-1647.
Phagocytosis of Staphylococcus aureus by macrophages exerts cytoprotective effects manifested by the up-regulation of antiapoptotic factors. Koziel et al, PLoS One (2009), 4:e5210.
Staphylococcus aureus an intracellular pathogen: the role of Small Colony Variants. Sendi and Proctor, Trends Microbiol (2009), 17:54-58
…
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A simple scheme ?
Cellular accumulation
Antibiotic
Antibacterial effect
Phagolysosomial infection
phagolysosomes
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1st exemple: Torezolid (TR-700), a novel oxazolidinone
3-{3-Fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-pyridin-3-yl]-phenyl}-5-hydroxymethyl-oxazolidin-2-one
O
N
O
HON
NN
NN
F
O
HN
O
N
O
N O
F
N-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide
TR-700 / DA-7157
linezolid
Comparative cellular accumulation
Torezolid accumulates quickly within cells, reaching an apparent cell. to
extracell. concentration ratio of 12.5 – 15.
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Torezolid vs. linezolid
Lemaire et al, JAC, 2009
Torezolid is more active than linezolid against
the intracellular forms of S. aureus (ATCC 25923)
On a weight concentration basis, torezolid is 4-fold more potent than linezolid against intracellular forms of S. aureus.
* Cs, Static concentration
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Torezolid vs. linezolid
Lemaire et al, JAC, 2009
When data are plotted against equipotent concentration (MIC multiples), torezolid and linezolid show undistinguishable concentration-dependent activities against intracellular forms of S. aureus
This indicates that the main driver of torezolid intracell. activity is not the marked cell. accum, but its higher intrinsic activity
Torezolid is more active than linezolid …Is it still true when comparing equipotent concentrations ?
Torezolid vs. Linezolid against others intracell. bacteria
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Cytosolic model Phagosomal model
MICs: L.M., TR-700, 0.125 mg/L vs LZD, 1 mg/L; L.P., TR-700, 0.25 mg/L vs LZD, 8 mg/L
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2nd exemple: CEM-101, a novel fluoroketolide
Comparative cellular accumulation
CEM-101 accumulates to a larger extent than clarithromycin (CLR) and telithromycin (TEL)
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CEM-101 vs. comparators
CEM-101 is more active than CLR and TEL against intracellular forms of S. aureus (strain ATCC 25923)
On a weight concentration basis, CEM-101 expresses consistently greater potency (decreases values of EC50 and Cs) and slightly higher efficacy (Emax) than comparators.
Lemaire et al, AAC (2009), 53:3734-3743
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CEM-101 vs. comparators
If we consider equipotent concentrations of antibiotics …
When data are plotted against equipotent concentration (MIC multiples), the differences in EC50 and static concentrations between drugs were minimized.
This indicates that the main driver of CEM-101 intracell. activity is not the marked cell. accum, but its higher intrinsic activity
* MICs at pH 7.4: CLR, 0.5 mg/L; TEL, 0.25 mg/L; CEM-101, 0.06 mg/L
*
Lemaire et al, AAC (2009), 53:3734-3743
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Is it still a simple scheme ???
Cellular accumulation
Antibiotic
These studies demonstrate the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects of TR-700 and CEM-101 whereas their
increased cellular accumulation per se play only a minimal role.
Antibacterial effect
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Other factors ???
Cellular penetration
Antibiotic
Metabolism
Binding Cooperation with host defences
Physical or biochemicalConditions prevailing
in the infected site
Influx vs. efflux Bacterial stress response
Thank you for your attention
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