Influence of conversion of penicillin G into a basic derivative on its accumulation and subcellular localization in cultured macrophages
beta-Lactam antibiotics do not accumulate in phagocytes, probably because of their acidic character. We therefore synthesized a basic derivative of penicillin G, namely, /sup 14/C-labeled N-(3-dimethylamino-propyl)benzylpenicillinamide (ABP), and studied its uptake and subcellular localization in J774 macrophages compared with that of /sup 14/C-labeled penicillin G. Whereas the intracellular concentration (Ci) of penicillin G remained lower than its extracellular concentration (Ce), ABP reached a Ci/Ce ratio of 4 to 5. Moreover, approximately 50% of intracellular ABP was found associated with lysosomes after isopycnic centrifugation of cell homogenates in isoosmotic Percoll or hyperosmotic sucrose gradients. The behavior of ABP was thus partly consistent with the model of de Duve et al., in which they described the intralysosomal accumulation of weak organic bases in lysosomes. Although ABP is microbiologically inactive, our results show that beta-lactam antibiotics can be driven into cells by appropriate modification. Further efforts therefore may be warranted in the design of active compounds or prodrugs that may prove useful in the chemotherapy of intracellular infections.
- Research Organization:
- Universite Catholique de Louvain, Brussels, Belgium
- OSTI ID:
- 6501297
- Journal Information:
- Antimicrob. Agents Chemother.; (United States), Vol. 3
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
PENICILLIN
BIOLOGICAL LOCALIZATION
UPTAKE
CARBON 14 COMPOUNDS
CELL CULTURES
LYSOSOMES
MACROPHAGES
MICE
STRUCTURE-ACTIVITY RELATIONSHIPS
TRACER TECHNIQUES
ULTRACENTRIFUGATION
ANIMAL CELLS
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
CELL CONSTITUENTS
CENTRIFUGATION
CONNECTIVE TISSUE CELLS
DRUGS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
ORGANOIDS
PHAGOCYTES
RODENTS
SEPARATION PROCESSES
SOMATIC CELLS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques