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Uptake and intracellular activity of AM-1155 in phagocytic cells
T Yamamoto1, H Kusajima, M Hosaka
1Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
Abstract:
The uptake and intracellular activity of AM-1155 in murine J774.1 macrophages and human polymorphonuclear leukocytes were investigated. AM-1155 penetrated phagocytic cells rapidly and reversibly, although the penetration process was not affected by metabolic inhibitors such as sodium fluoride, cyanide m-chlorophenylhydrazone, or ouabain or by nucleoside transport system inhibitors such as adenosine. The intracellular concentration-to-extracellular concentration ratio of AM-1155 in both cell types of phagocytes ranged from 5 to 7. These ratios were almost equal to those for sparfloxacin. The intracellular activity of AM-1155 in J774.1 macrophages, examined with Staphylococcus aureus 209P as a test bacterium, was dependent on the extracellular concentration. AM-1155 at a concentration of 1 microgram/ml reduced the number of viable cells of S. aureus ingested by more than 90%. The intracellular activity of AM-1155 was more potent than those of sparfloxacin, ofloxacin, ciprofloxacin, flomoxef, and erythromycin. These results suggest that the potent intracellular activity of AM-1155 might mainly be due to the high intracellular concentration and its potent in vitro activity.
Insights
AM-1155 effectively enters phagocytic cells, achieving high intracellular concentrations. This potent antimicrobial demonstrates superior activity against Staphylococcus aureus within macrophages compared to other antibiotics.
Area of Science:
- Pharmacology
- Cell Biology
- Microbiology
Background:
- Understanding the intracellular activity of novel antimicrobial agents is crucial for developing effective treatments against intracellular pathogens.
- Phagocytic cells like macrophages and neutrophils play a key role in host defense against bacterial infections.
Purpose of the Study:
- To investigate the uptake and intracellular activity of AM-1155 in phagocytic cells.
- To compare the intracellular efficacy of AM-1155 with established antibiotics.
Main Methods:
- AM-1155 uptake was studied in murine J774.1 macrophages and human polymorphonuclear leukocytes.
- Intracellular activity was assessed against Staphylococcus aureus 209P within macrophages.
- Inhibitor studies were conducted to elucidate the uptake mechanism.
Main Results:
- AM-1155 exhibited rapid and reversible penetration into phagocytic cells, independent of metabolic or nucleoside transport inhibitors.
- The intracellular to extracellular concentration ratio for AM-1155 was 5-7, comparable to sparfloxacin.
- AM-1155 demonstrated potent intracellular activity, reducing viable S. aureus by over 90% at 1 microgram/ml, outperforming sparfloxacin, ofloxacin, ciprofloxacin, flomoxef, and erythromycin.
Conclusions:
- The high intracellular concentration and potent in vitro activity contribute to AM-1155's significant intracellular efficacy.
- AM-1155 shows promise as a therapeutic agent for intracellular bacterial infections.