Antimycobacterial calixarenes enhance innate defense mechanisms in murine macrophages and induce control of Mycobacterium tuberculosis infection in mice.
Tuberculosis remains the leading cause of death among infectious diseases, accounting for more than two million deaths annually. The incidence of the disease is increasing globally, partially because of the resurgence of drug-resistant strains of Mycobacterium tuberculosis. Calixarenes are macrocyclic oligomers, some of which are able to modify the growth of M. tuberculosis in infected cells. Most experimental work has been carried out with Macrocyclon, also known as HOC 12.5EO. In this study, we demonstrate that Macrocyclon is effective in controlling M. tuberculosis infections, and we provide evidence that its effect is partially mediated by an l-arginine-dependent mechanism of macrophage activation that involves the activity of the inducible nitric oxide synthase. We also show that Macrocyclon is effective in athymic and major histocompatibility complex class II-/- mice and synthesized a number of structurally related calixarenes expressing significant antimycobacterial activity.
Colston
M Joseph
MJ
The National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Hailes
Helen C
HC
Stavropoulos
Evangelos
E
Hervé
Anne C
AC
Hervé
Gwenaelle
G
Goodworth
Kerry J
KJ
Hill
Alison M
AM
Jenner
Peter
P
Hart
Philip D
PD
Tascon
Ricardo E
RE
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001854:Bone Marrow Cells; D047250:Calixarenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D005260:Female; D008168:Lung / Q000382:microbiology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013154:Spleen / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*
D047250:Calixarenes; D011092:Polyethylene Glycols; C001664:Macrocyclon; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse