Intracellular Pharmacodynamics: a Journey from Cell biology to the Design of New Chemotherapeutic Agents Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology Unit Catholic University of Louvain, Brussels, Belgium & International Society of Antiinfective Pharmacology Advances in the Pharmacology of Antiinfective Therapy, Bangalore, India, January 20-22, 2000
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Intracellular Pharmacodynamics: a Journey from Cell biology to the Design of New Chemotherapeutic Agents Paul M. Tulkens, MD, PhD Cellular and Molecular.
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Intracellular Pharmacodynamics: a Journey from Cell biology to the Design of
New Chemotherapeutic Agents
Paul M. Tulkens, MD, PhDCellular and Molecular Pharmacology Unit
Catholic University of Louvain, Brussels, Belgium&
International Society of Antiinfective Pharmacology
Advances in the Pharmacology of Antiinfective Therapy,
Bangalore, India, January 20-22, 2000
What is Intracellular Infection ?
The Cell
(black box)
antibiotic bacteria
These they are… OBLIGATORY OR MAINLY INTRACELLULAR:
respiratory infections (pneumopathies): Chlamydia pneumoniae: 10% in children
Legionella pneumophila: frequent if immunosuppression Mycobacterium spp.: frequent if immunosuppression
sexually transmitted diseases Chlamydia trachomatis: most common pathogen
CNS infections + other sites: Listeria monocytogenes: pregnant women;
immunosuppression
FACULTATIVE OR MAINLY EXTRACELLULAR: digestive tract infections
1. where are the bacteria ? 2. which antibiotics accumulate in cells ?3. where are antibiotics located ?4. what is the intracellular expression of activity ?5. what is the bacterial responsiveness ? 6. cooperation with the cell own defenses and cytokines?
You need to consider (at least)the following questions:
1st question (and answer) : where do intracellular bacteria sojourn and thrive ?
LegionellaChlamydia, ...
S. aureusSalmonella,M. leprae, ...
Listeria hly+,Shigella
phagosomesphagolysosomes
cytosol endosomes
Antibiotics and Intracellular Bacteria : a Bit of Theory
Eur. J. Microbiol Infect. Dis. 10: 100-106, 1991
2d question (and answer): which antibiotics do accumulate in cells ?
• beta-lactams: 1x• aminoglycosides: <1 to 2 x• ansamycins: 2-3 x• tetracyclines: 2-4 x• fluoroquinolones: 10-20 x• macrolides: 4 to > 100 x