Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis also called Bacillus of Koch, from the name of the scientist who discovered it in 1882. There are 5 varieties: human, bovine, avian, murine, cold-blooded animals; of these only the first 2 are of importance in human pathology. Worldwide, TB is the leading infectious cause of morbidity and mortality in adults, and caused an estimated 1.5 million dead people in 2018, most of them in low- and middle-income countries. AIDS is the most important factor promoting tuberculosis infection and mortality, especially in areas with a high prevalence of the two infections. In Europe tuberculosis is relatively rare, the incidence is less than 10 cases / 100,000 inhabitants, a threshold within which a country is defined by the WHO as “low endemic”. In 2011 there were an estimated 8.7 million new cases and 10 million in 2017 overall, with 1.6 million deaths. The incidence of cases shows an important variability according to geographic area and socio-economic condition. India and China have the highest number of new cases, while South Africa has the highest incidence rate.
In 2007 there were about 13.7 million active chronic cases; 8.8 million new cases in 2010 and 1,450,000 deaths, mainly in developing countries. The absolute number of cases of tuberculosis has been decreasing since 2006 and new cases since 2002. But in recent years, however, numerous reasons for warning have emerged. The first of these is that in large metropolitan cities its incidence has increased up to 4-5 times greater than the average. This is followed by an increase in resistant bacterial strains (XDR-TB, extensively resistant forms, for which currently available drugs are not effective). The occurrence of epidemics at school level also occurred more and more frequently. Finally, a good portion of the cases identified and under pharmacological treatment do not complete the treatments, with the risk of being able to transmit the bacterium in the community.In the case of populations in developing countries, the possibility of contracting it comes from the fact that they often have a compromised immune system due to the high rates of AIDS cases.
Given that the old standard treatment protocols no longer work and that multi-resistant strains are gaining ground, are there drug options to address the problem? First of all, it should be noted that the duration of treatment is very long and often people with the disease do not complete the treatment cycle correctly. The therapy can indeed last from 6 months to 18-24 months. The incorrect use of antibiotics (with respect to the doses, the number of administrations, the time required), can cause the bacteria to adapt to the drugs and develop a real “resistance” to them. resistance to anti-tuberculosis drugs, WHO and the scientific associations have studied a strategy called DOT (Directly Observed Therapy), which ensures that the patient takes the drugs every day. With this type of therapeutic treatment, followed “diligently”, the treatment period for tuberculosis is reduced to about 6-8 months. Introduced in the 1990s, DOT is currently considered one of the most effective methods for treating TB and preventing the onset of antibiotic resistance. In almost all areas of the world, today there is a form of tuberculous disease called MDR-TB (multidrug resistant), resistant to the most effective antibiotics for the treatment.
It is up to the physician to decide on the most suitable therapy based on the examinations and the patient’s medical history. The anti-tuberculosis drugs used today are: isoniazid, ethambutol, rifampicin, pyrazinamide and streptomycin, in various combinations, both for “attack” and maintenance therapy. Once started, treatment with anti-tuberculosis drugs must be followed scrupulously and accompanied by control tests. Therapy should be started in specialist clinics or in hospital for more complex or severe cases. Due to the emergence of MDR-TB, several innovative drug options have been under consideration for a decade. For example, Pretomanid was first identified in 2000 in a series of 100 nitro-imidazopyrane derivatives synthesized and tested for TBC activity by Novartis. Pretomanid was approved by the FDA in the United States in 2019 only in combination with bedaquiline and linezolid for the treatment of a limited and specific population of adult patients with largely drug resistant. Its derivatide delamanid is under investigation. Sutezolid is a linezolid analogue antibiotic currently under development as a treatment for MDR tuberculosis. It differs from linezolid by replacing the oxygen of the morpholine portion with a sulfur atom. This very slight modification kills intracellular mycobacteria but its sulfoxide derivative kills those not yet phagocytosed (external).
There are other anti-tuberculosis drugs that are making a comeback: these are molecules used more often in the past and almost completely abandoned after the introduction of standard drugs. Ethionamide, thiocarlide (or Isoxyl) and thioacetazone are mentioned. All these old anti-tuberculosis drugs inhibit the synthesis of mycolic acids, which are essential for building the thick bacterial wall. They target certain enzymes of the aforementioned enzyme pathway, but due to the easy emergence of resistance against them, research is engineering these molecules to be less inactivable and to target more than one target enzyme (multi-targeting). Even the old disinfectant triclosan targets an enzyme of this biosynthesis (InhA). An attractive target is the bacterial protein EthR, which regulates the production of these enzymes. Experimental inhibitors of this protein have already been synthesized, based on the skeleton of oxydiazole, thiadiazole and semicarbazone. All of them have very high affinities for the EthR protein and appear to be more effective in vitro than the drugs mentioned above.
But the known metabolic pathways are not the only ones to be targeted: by deepening the biochemistry of bacterial metabolism, new potential molecular targets emerge. The pathway of purine synthesis is essential for bacterial reproduction, but presents difficulties given the enzymatic analogy of the animal or human counterpart. This is why inhibitors of the IMPDH pathway (VCC23471899) and folic acid (BWR992010, H37Ra) have been developed. The old antibacterial trimethoprim, often used in combination with sulfonamides, was also found to be active against mycobacteria but not effective and easily inactivated. To target these biosynthetic pathways, both the QSAR (quantitative structure-activity relationship), in-silico modeling and drug repurposing approaches were adopted. This way it has been possible to discover, for example that some carbapenem antibiotics (like tebipenem) fluoroquinolones (gatifloxacin, moxifloxacin), antiparasitic or antimalarics (clofazimine, mefloquine, niclosamide, nitazoxanide) and even some NSAIDs like ibuprofen, carprofen and celecoxib have resulted active in biomolecular assays.
Therefore, finally after decades of silence necessity will drive science toward new horizons. After all, evolution is the spring to fulfill every need.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Dott. Gianfrancesco Cormaci
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