Director of Studies Jason Carlyon. (Credit: Virginia Commonwealth University)
A variety of microbial rebounds threaten human health. So far, antibiotics are taking full advantage of the bacteria. However sleeping on the laurels is not in place, as creatures can adapt to drugs. Keeping leadership ahead will depend on efforts to find new ways to fight.
Scientists at Virginia Commonwealth University and their associates at four other universities located in the United States contributed to the effort to maintain leadership. In the disclosed disclosures, some antidepressants inhibit the growth of at least four intracellular parasitess.
In human cell lines in the tube and even in a microbe type in vivo, the mice examined the antimicrobial effect of the tricyclic antidepressant desipramine. They also discussed the mechanisms action on individual microbial species and their developmental stages.
They received excellent bacteriostatic results against bacteria in the testsI Phagocytophilum Anaplasma induce human granulocytic anaplasmosis, which may end up in elderly patients with lower immune function and without antibiotic intervention death. The infection is transmitted by ticks and although the disease is rarely known as other diseases associated with ticks, it can also be detected in the Czech Republic.
Parasite Anaplasma p. It infects white blood cells. (CC BY-SA 3.0)
Likewise, desipramine rotated well with the microorganism Creator of Coxiella burnetii Q fever. However, a rare zoonosis is common in humans in farm and domestic animals. Most of the time, it is obtained from animals by the inhalation of contaminated dust or not by ingestiontreated products of animal origin. As a result very low infectious doseky and Persianand in the environment has been tested in onemeric soldiers under the Biological Weapons Development Program. That there is no exotic sound of Q in Europethey unprecedented subjects 4000 registered cases between years 2007 – 2010 in the Netherlands.
Only the last mentionednto Chlamanddiim, because the experiments with them did not go so well. Chlamydia trachomatis, which causes nmore common ifxinfectious urogenital tract infections, was statistically significant inhibitedbut the inhibition rate did not arrive biological Relevance The test was betterone with a slower-growing pathogen Chlamydia pneumoniae specialists respiratory infections system. U his cure for delusions had partially suppressed reproduction.
The bottom chart shows the number of copies of the genetic information Anaplasma p. in the blood of infected mice, depending on the time of infection. The blue label belongs to the control group of animals and the red group to which desipramine was administered. Infection in the group below the influence of antidepressant did not inflame at all. The top chart shows almost the same. Only the absence of the enzymatic function is congenital in ASM – / – mice (red marking), making them resistant. Similarly, in humans, we know of the hereditary Niemann-Pick disease caused by ASM deficiency. So they must also be immune to infection. (Credit: DOI: 10.26508 / lsa.201800292, CC BY 4.0)
The remarkable antimicrobial properties discovered indicate that they may have antidepressantsone to replace antibiotics with anaplasmaOzy possibly Q fever. Although tested pathogens are generally susceptible to appropriate antibiotics.is one acute Infection, if the situation so requires, usually resolves its administration in the short term, records the potential willingness to make clinical research several hypotheses in the future. Especially, desipramine does not directly damage the parasite, but it does influence the fate of cholesterol in the host cell that does not control the pathogen. For this reason, it is probably excluded that he would have adopted some mechanism of easily obtained adaptation against him.
In addition, any measure to reduce the consumption of classical antibiotics limits the selection of resistant germs. In addition, the narrow spectrum substance does not affect the patient's natural and beneficial microbe. Both properties would be even more useful in the treatment of chronic infections. Due to the different way of life of pathogens, it can sometimes be difficult eradicate of the human body. The presence of an antibiotic will prevent proliferation, but bacteria with low metabolic activity will not kill. Hiding internal cells with loss of capacity apoptosis intruders protect against the immune system. They can then survive in the body for a long time and under favorable conditions begin a new offensive. For example, when Q fever goes into chronic form, treatment requires a minimum of 18 months of antibiotic intake.
As already explained,is the therapeutic despair does not force the clinical research to be performed and the indications for expanded desipramine. It's nothing, too. and does not see any financial benefit to pharmaceutical companies.. On the other hand, for the long-term use of a registered drug, to obtain evidence for the approval process and for the administration itself, compared with some experimental compound should go to the left.
The authors have not yet verified all the representatives for whom with ink hit in black. If antidepressant blocks parasites Ehrlichia chaffeensis, Toxoplasma gondii one Brucella abortus, waiting to be answered. Neither the partial suppression observed with β can be ruled out Chlamydia pneumoniae. It will definitely be necessary combination P common antibiotic. This would definitely increase success rate treatment and reduce the likelihood of developing resistance.
Other drugs approved with the same effect
While the subject requires intracellular parasites that live inside host cells are bacteria, its strategy is reminiscent of mannerismand virus. To create a new generation, they must enter the cell and enslave it your benefit. To produce Unlike viruses, proteins lead by their own device. What they need to steal (ATP) arises in the mitochondria that they lost during coevolution. Although they have the tools to guarantee a great autonomy in the synthesis of building materialsyou, they seem to actively collect cholesterol to build a separation sheath is in cytoplasm host cells, and suffers from discomfort if this process is disrupted.
The graph shows the proliferation of chlamydia in cell culture. C. trachomatis is slightly inhibited (black bar) against the control (white bar). U C. pneumoniae the inhibition is more pronounced. (Credit: DOI: 10.26508 / lsa.201800292, CC POR 4.0)
In the cell, cholesterol can come from within (synthesis) or from the outside. In the second case, which is fundamental for the desipramine function, cholesterol retains the cellular receptors in the form of LDL particles. The trapped lipid is then transported on mobile organelles lysosome where it undergoes hydrolysis. This chemically reformulated is used by the host cell. The bacteria then lurk in the finished material leaving the lysozyme.
About cholesterol hydrolysis v lysosome the old protein bound to the inside of the cell organelle membrane, calledfingomyelinase (ASM). It is the inhibition of ASM that interrupts the pathway and closes the parasite with a cholesterol bypass. The microbial disorder clears the biological manifestation of a broader group of substances, including desipramine. They carry the abbreviated name FIASMAs (functional inhibitors of acid sphingomyelinase).
The method of inhibiting ASM by FIASMAs is more detailed. The FIASMAs in neutral form penetrate the acidic environment of the lysosome and form cations that form the lysosome organelles they can not escape. Therefore, in lysozandaccumulate one under the stick, the lipophilic interactions adhere to the inner side of the negatively charged membrane. As they carry a positive charge, they line up with the opposite signal on the membrane, thereby isolating the binding force from the ASM to the substrate. So far, the anchored ASM will lose ground and the released protein will subsequently relentlessly destroy proteolytic events.
The principle of inhibition implies that FIASMAs may not be strict configuration keys to block like other inhibitors. Úpjust enough to structure showed a weak lipofand basic properties. Therefore exist many of these substances limitI approved medicines, but not all are equally effective. Z registered drugs include all tricyclic antidepressants and SSRIs, some antipsychotics, antihistamines, antihypertensives and others. In short, there is plenty to choose from and perhaps they hiding the future helper to control various selected infectious diseases.
DOI: 10.26508 / lsa.201800292