Antimicrobial activities of clofazimine and B669 are mediated by lysophospholipids.
The susceptibilities of a range of gram-positive and gram-negative microbial pathogens to clofazimine and its analog B669 (0.1 to 32 micrograms/ml), as well as the effects of these agents on membrane phospholipid metabolism in Staphylococcus aureus and Escherichia coli, have been investigated in vitro. Gram-positive bacteria were found to be generally susceptible to these agents, whereas gram-negative organisms were uniformly resistant. Exposure of S. aureus to both agents (1 to 5 micrograms/ml), especially B669, caused dose-related enhancement of the activity of phospholipase A2, according to an increase in the release of 3H-radiolabeled arachidonate and lysophosphatidylethanolamine ([3H]LPE) from bacterial-membrane phospholipids. Treatment of E. coli with the riminophenazines also increased the release of [3H]arachidonate and [3H]LPE. Growth of gram-positive but not gram-negative bacteria was inhibited by LPE and lysophosphatidylcholine. Moreover, coincubation with alpha-tocopherol (vitamin E), a lysophospholipid complex-forming agent, or with lysophospholipase protected gram-positive bacteria against the riminophenazines as well as against lysophospholipids. The results from this study are consistent with a mechanism whereby lysophospholipids mediate the activities of the two drugs.
Van Rensburg
C E
CE
Department of Immunology, University of Pretoria, Republic of South Africa.
Jooné
G K
GK
O'Sullivan
J F
JF
Anderson
R
R
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002991:Clofazimine / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D006131:Growth Inhibitors / Q000494:pharmacology; D008245:Lysophospholipase / Q000378:metabolism / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D013056:Spectrophotometry, Ultraviolet
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D006131:Growth Inhibitors; D008246:Lysophospholipids; D002991:Clofazimine; D010741:Phospholipases A; D054467:Phospholipases A2; D008245:Lysophospholipase