Researchers at Virginia Commonwealth University presented the findings of their study published in Life Science Alliance that certain antidepressants may have the potential to treat infections with intracellular microorganisms. These drugs, known as functional inhibitors of acid sphingomyelinase (FIASMAs), interfere with acid sphingomyelinase (ASM), an enzyme that aids in the release of LDL cholesterol from the lysosome. The activity of ASM is an integral part of the infectious process with intracellular microorganisms because they target cholesterol within the cells. The FIASMAs analyzed in this study were desipramine, amitriptyline, and nortriptyline, which belong to the drug class, tricyclic antidepressants.
"Since FIASMAs influence cholesterol trafficking in the cell and cholesterol plays a role in so many facets of our biology, they have been used to treat a wide variety of conditions and diseases," Carlyon said.
Anaplasma phagocytophilum, Coxiella burnetii, Chlamydia trachomatis, and Chlamydia pneumoniae were used to demonstrate that the activity of ASM is a vital part of the infectious process. The four organisms are "obligate intracellular vacuole-adapted bacterial pathogens that target host cholesterol trafficking pathways" and are responsible for the diseases human granulocytic anaplasmosis, Q fever, pneumonia, and a sexually transmitted infection.
The findings of the study demonstrated that ASM inhibition was more effective with desipramine when testing A.phagocytophilum and C. burnetii than the other two organisms. Desipramine was less effective with C. pneumoniae since it uses sources of both LDL cholesterol and non-LDL cholesterol during its growth cycle. C. trachomatis showed even less inhibition than C. pneumoniae.
"It would be highly beneficial to have a class of drugs to treat such diseases in patients for whom tetracyclines are contraindicated," Carlyon said. "These drugs could provide an alternative to antibiotics or even be used in conjunction with them as an augmentation approach to treat infections that typically require prolonged courses of antibiotic therapy, such as those caused by Chlamydia pneumoniae and Coxiella burnetii."
Carlyon went on to state that: "What is so exciting about this study is that the class of drugs we evaluated targets an enzyme in our cells regulating cholesterol, not the bacteria," Carlyon said. "I do not envision the pathogens being able to develop resistance to this treatment because it is targeting a host pathway that they very much need to grow and survive inside of the body."
The researchers suggest that, since these drugs are likely to prevent resistance, they should be evaluated clinically as an alternative to antibiotics or in conjunction with one to augment their efficacy.
