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REVIEWS 39 Medicina (Kaunas) 2011;47(Suppl 2):39-48 Structure-Activity Relationships of Antituberculins Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius Department of Drug Chemistry, Medical Academy, Lithuanian University of Health Sciences, Lithuania Key words: tuberculosis; Mycobacterium tuberculosis; antitubercular drugs. Summary. Tuberculosis caused by Mycobacterium tuberculosis remains the leading cause of mortality worldwide in the 21st century. The multidrug therapy to treat tuberculosis patients was introduced more than 50 years ago mainly because of the emergence of drug resistance. The mortality and spread of tuberculosis has been further aggravated because of the synergy of this disease with HIV. A number of antitubercular drugs are ineffective against this disease because of the development of drug-resistant strains. Unfortunately, most drugs that are used today for the treatment of tuberculosis were developed 40 or more years ago. Therefore, tuberculosis was the focus of renewed scientific interest in the last decade. This article provides a brief review of the drugs currently used in the treatment of tuberculosis and the most advanced compounds undergoing preclinical or clinical trials. A short description of the mechanisms of their action on related biochemical targets is also presented. Introduction Tuberculosis (TB) is an old disease that is thought to have evolved sometime between the seventh and sixth millennia BC. In 1882, Robert Koch discovered the tubercle bacillus Mycobacterium tuberculosis (MTB), the organism that causes TB. TB remains an important public health problem worldwide and in the European region (Fig. 1). One of the aims of the World Health Organization (WHO) is to reduce morbidity rates and death rates caused by TB in 18 high-priority countries of Eastern Europe. The plan to reach this aim includes 6 targets for the year 2010 (1): 1. To reach 100% DOTS (directly observed treatment, short-course) population coverage in all eastern European countries; 2. To increase the detection rate of new infectious TB cases to at least 73%; 3. To achieve treatment success in at least 85% of detected new infectious TB cases; 4. To provide treatment according to internationally recommended guidelines in 100% of multidrug-resistant TB cases, both new and previously treated; 5. To reduce the prevalence of all TB forms to 188 cases per 100 000 population; 6. To decrease the mortality rate of all TB forms to 16 deaths per 100 000 population. The Deteriorating Situation of TB/HIV and Multidrug-Resistant TB combination Coinfection with TB and HIV has been shown Correspondence to L. Šlepikas, Department of Drug Chemistry, Medical Academy, Lithuanian University of Health Sciences, A. Mickevičiaus 9, 44307 Kaunas, Lithuania E-mail: [email protected] to be a lethal combination. According to the alarming data from the WHO, TB is the leading cause of mortality in people with HIV. People who are HIVpositive and infected with TB are 20 to 40 times more likely to develop active TB than people not infected with HIV. In 2008, 1.8 million people died from TB including 500 000 people with HIV. Another factor contributing to the rise in TB infections and, consequently, to the increased number of deaths is the emergence of multidrug resistance (MDR) (2–4). According to the data collected during the last decade, 5% of all TB cases have MDRTB. Three treatments used in practice have been at least partly successful in the control of the illness: • The sanatorium with fresh air and nutrition (not discussed in this publication); • Vaccination; • Chemotherapy. Vaccination Active immunization is one of the most important treatments to control TB, but in most cases, it is still ineffective today. The bacille Calmette–Guérin (BCG) vaccine has existed for 80 years and has been one of the most widely used of all current vaccines. The impact of BCG vaccination on the transmission of TB is limited, because it does not prevent primary infection and, more importantly, does not prevent reactivation of latent pulmonary infection, the principal source of bacillary spread in the community. Adresas susirašinėti: L. Šlepikas, LSMU MA Vaistų chemijos katedra, A. Mickevičiaus 9, 44307 Kaunas El. paštas: [email protected] Medicina (Kaunas) 2011;47(Suppl 2) 40 Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius Cases per 100 000 Population 80 70 Eastern Europe (18 Countries) European Region (53 Countries) EU (With Enlargements) 79 60 50 41 40 30 20 12 10 0 1980 1985 1990 1995 2000 2005 Year Fig. 1. TB notification rates in the European Region, 1980–2005 (1) Chemotherapy Various agents have been discovered for the treatment of tuberculosis since the 1940s when streptomycin and p-aminosalicylic acid were introduced. The common antitubercular drugs used in treatment are first-line and second-line drugs. First-line drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) have high antitubercular efficiency and low toxicity compared with second-line drugs (thiacetazone, p-aminosalicylic acid, ethionamide, prothionamide, cycloserine, amikacin, kanamycin, ciprofloxacin, levofloxacin, moxifloxacin, and floxacillin), which have lower efficiency, and/or higher toxicity. Many current antitubercular agents interact with the macromolecules inactivating biosynthesis pathways: Inhibitors of fatty acid biosynthesis (Fig. 2) • Isoniazid (INH) • Pyrazinamide (PZA) • Ethionamide (ETA) • Prothionamide (PRO) Inhibitors of arabinogalactan and peptidoglycan biosynthesis (Fig. 3) • Ethambutol (ETH) • D-Cycloserine (CYS) Inhibitors of protein synthesis (Fig. 4) • Streptomycin (STR), kanamycin, amikacin • Clarithromycin (CLA) • Linezolid (LIN) Inhibitors of DNA-based processes (Fig. 5) • Rifamycins (RPM): rifampicin (RIF), rifapentine (RIFAP), rifalazil (RIFAL), rifabutin (RIFAB) • Fluoroquinolones: moxifloxacin (MOXI), ciprofloxacin (CIP), levofloxacin (LEV), ofloxacin (OFL), gatifloxacin (GATI). Inhibitors of dihydrofolate reductase or siderophore biosynthesis (Fig. 6): • p-Aminosalicylic acid (PAS) According to the latest literature data, apart from some of the abovementioned targets, which are still in the process of being established, other potential targets exist: inhibitors of the proton pump F0F1H+ATPase (5–9); inhibitors of mycobacterial cytochrome P450 monooxygenases (10–14); FtsZ targeting compounds (15–23); inhibitors of branched-chain amino acid biosynthesis (24–26), nucleoside monophosphate kinase inhibitors, pyrimidine or purine nucleoside analogues (27–32); signaling kinase inhibitors (33–38); and miscellaneous mechanism-based inhibitors (37–41). Current antitubercular drugs Isoniazid. INH was first synthesized in 1912 and for the first time used in clinical practice in 1952. INH is a prodrug activated by catalase-peroxidase hemoprotein, KatG. As an inhibitor of fatty acid biosynthesis, INH inhibits the mycolic acid biosynthesis in MTB by affecting an enzyme mycolate synthetase, unique for MTB. INH is orally active and exhibits bacteriostatic action on resting bacilli and is highly active against M. tuberculosis, M. bovis, M. atricanum, and M. microti. Activity of IHN against these pathogens is 0.02–0.06 μg/mL (42). The risk of developing severe hepatitis and liver toxicity is associated with INH usage. This risk is higher in patients who take drugs like carbamazepine, phenobarbital, and RIF, abuse alcohol and older people. Pyrazinamide. An isostere of INH, the synthetic molecule PZA, was first synthesized in 1936; since 1985, this compound has been the third most important antitubercular drug. The activity of PZA depends on the presence of bacterial amidase, which Fatty Acid Biosynthesis Inhibitors Fig. 2. Drugs acting as inhibitors of fatty acid biosynthesis Medicina (Kaunas) 2011;47(Suppl 2) Structure-Activity Relationships of Antituberculins converts PZA to pyrazinoic acid (POA), the active anti-TB molecule. The accumulation of POA and protonated POA lowers the intracellular pH to a suboptimal level that may inactivate many pathways including fatty acid synthase and membrane transport function. However, it is widely accepted that POA may not have a specific target, but rather that cellular acidification causes the inhibition of major processes. In vitro activity of PZA against MTB is 6–50 μg/mL at pH 5.5; MIC90 at pH 5.5 is 50 μg/ mL, at pH 5.8 is 100 μg/mL, and at pH 5.95 is 200 μg/mL (43). The primary adverse effect of PZA is a hepatic reaction. Hepatotoxicity is dose related and may appear at any time during drug therapy. PZA is contraindicated in persons with severe liver damage or with acute gout. Ethionamide and Prothionamide. The mode of action of the activated form of ETA is via inhibition of the inhA gene product enoyl-ACP reductase. In vitro activity of ETA and PRO against MTB H37Rv is 0.25 μg/mL and ~0.5 μg/mL, respectively(42). ETA is active against M. tuberculosis, M. bovis, and M. smegmatis. ETA is also active against M. leprae. PRO is active against mycobacterial species including M. leprae and M. avium (44). It was found that PRO killed M. leprae more quickly than ETA did (45). The most common side effects are nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight loss. PRO should be avoided during pregnancy or in women of childbearing potential. Hepatotoxic effects of ETA are common and occur at a fairly high rate although they tend to be less serious than those of the related drug PRO. The most common adverse reactions of ETA and PRO are dose-related gastrointestinal disturbances, anorexia, excessive salivation, metallic taste, nausea, vomiting, abdominal pain, and diarrhea. Disturbances of the central nervous system (CNS) include depression, anxiety, psychosis, headache, postural hypotension, and asthenia. 41 Arabingalactan and Peptidoglycan Biosynthesis Inhibitors Fig. 3. Drugs acting as inhibitors of arabingalactan and peptidoglycan biosynthesis Ethambutol. ETH is a synthetic amino alcohol first used in the treatment of TB in 1966. ETH inhibits arabinosyl transferases involved in cell wall biosynthesis. ETH is effective against actively growing MTB microorganisms. Nearly all strains of M. tuberculosis, M. kansasii, and M. avium are sensitive to ETH. In vitro potency against MTB H37Rv is 0.5 μg/mL (S,S form is 600 times more active than R,R) (42). Optic neuropathy and occasional hepatotoxicity are common. Optic neuropathy including optic neuritis or retrobulbar neuritis occurring in association with ETH therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. D-Cycloserine. CYS is an analogue of the amino acid D-alanine. CYS inhibits alanine racemase (Alr, converts L-alanine to D-alanine) and D-alanine ligase (Ddl), which synthesize the pentapeptide core using D-alanine; both enzymes are essential in the synthesis of peptidoglycan and, consequently, in cell wall biosynthesis and maintenance. CYS is a broad-spectrum antibiotic, which inhibits MTB at concentrations of 5–20 μg/mL (42). CNS toxicity is dose-related and shows neuropsychiatric effects like drowsiness and slurred speech. Symptoms of CYS overdose are generally neuropsychiatric and include convulsions, seizures, slurred speech, paralysis, and unconsciousness. Inhibitors of Protein Synthesis Fig. 4. Drugs acting as inhibitors of protein synthesis Medicina (Kaunas) 2011;47(Suppl 2) Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius 42 Rifapentine Rifalazin Rifampicin Rifabutin Inhibitors of DNA-Based Processes Ciprofloxacin Gatifloxacin R/S: Ofloxacin S: Levofloxacin Moxifloxacin Fig. 5. Drugs acting as inhibitors of DNA-based processes Inhibitors of Dihydrofolate Reductase or Siderophore Biosynthesis p-Aminosalycilic Acid Fig. 6. Drug acting as inhibitors of dihydrofolate reductase or siderophore biosynthesis Streptomycin. The chemotherapy with STR introduced in 1946 by its combination with others anti-TB agents, such as p-aminosalicylic acid and isoniazid. STR was the first aminoglycoside antibiotic isolated from Streptomyces griseus. It inhibits protein synthesis by binding tightly to the conserved A site of 16S rRNA in the 30S ribosomal subunit, and its use can lead to the selection of overlapping cross-resistant MTB strains (46). Streptomycin is active against MTB H37Rv (MIC, 1 μg/mL) and a number of clinical M. tuberculosis strains including an MDR strain with resistance to INH and RIF (42). Moreover, STR is least toxic in the aminoglycoside class. Many toxic effects appear on the peripheral and central nervous system; the frequency of neurotoxic reactions (cochlear and vestibular dysfunction, optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy) increases in patients with impaired renal function or prerenal azotemia. Accordingly, STR is contraindicated in patients with renal impairment. Aminoglycosides remain important drugs for treating diseases caused by MTB, but they are no longer first-line drugs because the growing resistance is unacceptably rapid. Clarithromycin. CLA, a macrolide antibiotic similar to erythromycin and azithromycin, binds to the 50S ribosomal subunit resulting in inhibition of protein synthesis (47). In vitro potency against MTB H37Rv is 8 μg/mL at pH 7.4 (42). MIC against a panel of clinical MTB isolates is 1.3–10 μg/mL compared with >10 μg/mL for erythromycin. CLA has relatively poor in vitro activity against M. tuberculosis, but has better activity against M. avium (MIC90, 8 μg/mL) and M. kansasii (MIC90, ≤0.5 μg/ mL). CLA is 8 to 32 times more active than erythromycin against M. avium (42). CLA should not be used during pregnancy due to adverse effects seen in fetal development in monkeys, rats, and mice. The most common adverse effects are gastrointestinal (diarrhea, vomiting, abdominal pain, and nausea); headache and rash are common as well. Linezolid. LIN is the first in a new class of oxazolidinone antibiotics and inhibits protein synthesis. LIN binds to 23S rRNA inhibiting translation in the Medicina (Kaunas) 2011;47(Suppl 2) Structure-Activity Relationships of Antituberculins early phase and preventing the proper binding of formyl-methionine tRNA. In vitro potency against MTB H37Rv is 0.25 μg/mL. LIN is active against MDR M. tuberculosis strains (48). LIN causes reversible myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) in patients especially when the drug is administered for prolonged periods. The most common adverse events in patients treated with LIN were diarrhea, headache, and nausea. Rifamycins. RPMs are a group of semisynthetic antibiotics of rifamycin B isolated from Streptomyces mediterrani. This class of drugs inhibits bacterial RNA synthesis by binding to the β subunit of the DNA-dependent polymerase and has no effect on mammalian enzymes. The lipophilic properties of the molecule are important for binding of the drug to the polymerase and helping the drug in its transport across the mycobacterial cell wall. RPM is bactericidal with a very broad spectrum of activities against most gram-positive and some gram-negative organisms. RMP is effective against MTB H37Rv with the following MICs: RIFAP, 0.031 μg/mL; RIFAB, <0.015 μg/mL; RIF 0.25, μg/mL; and RIFAL, <0.015 μg/mL (49). Many RIF-resistant MTB mutants are cross-resistant with RIFAP and RIFAB, but others do show some differential sensitivity. Hepatitis and serious hypersensitivity reactions including thrombocytopenia, hemolytic anemia, and renal failure have been reported (50). Hepatotoxicity is generally rare and probably not associated with the rifamycins alone but it manifests with these drugs in combinations with other TB treatments. Fluoroquinolones. Fluoroquinolones are part of the family of synthetic derivatives of nalidixic acid with broad-spectrum antimycobacterial activity. Their bactericidal action occurs due to the inhibitory effects of ATP-dependent enzymes, topoisomerase II (DNA gyrase), and topoisomerase IV that are involved in the several processes, such as DNA transcription and multiplication in Mycobacteria. Several members of this class have been used as the second-line drugs for the treatment of MDR TB. Gatifloxacin and moxifloxacin have shown better in vitro activity against MTB than the older fluoroquinolones, i.e., ofloxacin and ciprofloxacin. In vitro activity of MOXI against MTB H37Rv is MIC 0.5 μg/ mL (51). Comparative MICs for others quinolones are as follows: CIP, 0.5 μg/mL; OFL, 0.71 μg/mL; LEV, 0.35 μg/mL; and GATI, 0.125 μg/mL. MOXI is more active against M. kansasii than M. avium complex. Prolongation of the QT interval is a general feature of the action of fluoroquinolones. Quinolones are associated with specific tendinitis-type events, and LEV seems to be associated with the highest rates among these drugs. p-Aminosalicylic Acid. The treatment of tubercu- 43 losis started in the 1940s when para-aminosalicylic acid and streptomycin were introduced in practice. Interestingly, it has no effect against other bacteria, but it is highly effective against MTB. One of the suggested action modes of PAS is the interference process with iron acquisition by the salicylatedependent biosynthesis involved in iron uptake in Mycobacteria. PAS is bacteriostatic. The MIC of aminosalicylic acid against MTB is <1.0 μg/mL for 9 strains including 3 MDR strains, but 4 and 8 μg/ mL for 2 other MDR strains. PAS is inactive in vitro against M. avium (52) and is contraindicated in patients with serious renal disease due to accumulation of toxic metabolites. Compounds Under Preclinical or Clinical Trials. No new drug classes have been introduced into the treatment of tuberculosis over the past 50 years (53). In recent years, a scientific approach, using genetic engineering of MTB, played an important role for validation and screening new libraries of compounds to determine more effective anti-TB agents. The fluoroquinolones mentioned in this review are only a few representatives of the family of at least 25 related antibacterials currently used in preclinical and clinical trials or in practice (Fig. 7). PD-161148 and CS-940 have been selected based on their potent broad-spectrum activity against gram-negative, gram-positive, and anaerobic bacteria. CS-940 was screened against 100 clinical isolates of MTB and was found to have an average MIC of 0.25–0.5 μg/mL and to be more potent than ofloxacin, ciprofloxacin, and balofloxacin. PD-161148 was also tested against various clinical isolates of MTB, where it was compared with the desmethoxy analogue and ciprofloxacin and showed to be 3 to 4 times more active. Quinolone sitafloxacin (DU-6859a) is under Fig. 7. The most active derivatives of fluoroquinolones against Mycobacterium tuberculosis Medicina (Kaunas) 2011;47(Suppl 2) 44 Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius trials in Japan and the United States. Sitafloxacin was found to be equipotent with gatifloxacin and sparfloxacin; it is more active than levofloxacin and ofloxacin when tested against MTB – MICs at which 90% of strains of MTB inhibited were ~0.2 μg/mL. T-3811ME is unique among the other broad-spectrum quinolones because it lacks the presence of a fluorine atom at the 6-position of the ring. Against 10 strains of MTB, T-3811ME has an MIC90 value of 0.0625 μg/mL. The oxazolidinone class of antibiotics is a new promising class of synthetic antimicrobial agents with a unique mechanism of action in inhibiting protein synthesis (Fig. 8). The first antibiotic of oxazolidinone class – linezolid (U-100766) – is approved and also is being studied for the treatment of MDR TB. Oxazolidinones PNU-100480 containing a thiomorpholine moiety in place of the morpholine unit present in linezolid have been reported to be particularly active against MTB with MICs of 0.125 μg/mL. The Dong-A Pharmaceutical has reported several new oxazolidinones (DA7157, DA-7218, and DA-7867) having somewhat improved in vitro potency, compared with linezolid against M. tuberculosis, M. kansasii, and M. marinum (54–55). According to literature data, one of the most advanced oxazolidinones is ranbezolid (RBx 7644) (56), which was tested in clinical trials in 2004 (57). Moreover, the presence of a nitro group on its structure raises the question whether their activity is due to the inhibition of the ribosome or to another mechanism related to the many nitro-bearing antibacterials. Other oxazolidinones, such as the AstraZeneca compound AZD 256387, are being progressed clinically for the treatment of MDR bacterial infections (58). It was reported in the late 1990s that a series of antimycobacterial pyrroles demonstrated significant in vitro and in vivo activity against sensitive and resistant strains of MTB. After identification of the initial compound BM 212, further structure-activity studies were undertaken in vitro, and compound (I) was shown to have an effect on the mycobacterial growth inside the macrophages (Fig. 9). Another research group also carried out structural optimization studies, and the isoniazid-bearing derivative (II) was shown to be active in vivo on a murine model infected with resistant MTB strains (59). However, Fig. 8. The most active derivatives of oxazolidinones against Mycobacterium tuberculosis Pyrroles and Pyrroles With Isoniazid-Bearing Derivatives Fig. 9. The most active derivatives of pyrroles against Mycobacterium tuberculosis Medicina (Kaunas) 2011;47(Suppl 2) Structure-Activity Relationships of Antituberculins 45 Nitroimidazo-Oxazine and Nitroimidazo-Oxazole Derivatives Fig. 10. The most active derivatives of nitroimidazo-oxazine and nitroimidazo-oxazole against Mycobacterium tuberculosis the presence of an isoniazid-bearing derivative, as a pharmacophoric unit, on its structure raises the question which part is active. The latest compound LL-3858 is in progress of preclinical studies. Literature data have reported (60–61) that in vitro activity of LL-3858 against MTB is 0.12–0.025 μg/mL. The first bicyclic nitro-bearing imidazoles were reported in the late 1970s (62). The Ciba-Geigy 5-nitroimidazole derivative CGI-17341 showed a considerable potential for the treatment of TB (Fig. 10). In vitro, at 0.04 to 0.3 μg/mL, the compound inhibited both drug-susceptible and MDR strains of MTB and showed no cross-resistance with INH, RIF, STR, or ETH (63). Further work with the nitroimidazooxazine family led to recognition of the effect it has on MTB, which led to the discovery of PA-824. PA-824 has in vitro potency of 0.15–0.3 μg/mL against MTB H37Rv compared with 0.03 μg/mL of INH. PA-824 has very specific activity, possibly due to its unique reducing activity; it appears to be limited to the MTB complex as there is very limited efficacy against M. smegmatis and M. avium. OPC-67683 is closely related to PA-824 and may share a similar mode of action. It has in vitro potency against MTB H37Rv (0.012 μg/mL) (64). OPC-67683 is described as mycobacteria-specific; moreover, it is active against M. kansasii and M. tuberculosis, while PA-824 showed activity only against M. tuberculosis (65). Phase I OPC-67683 clinical trial has been performed in Japan since 2006. The broad and potent activity of 4-thiazolidinones has established them as one of the biologically important pharmacophoric units (Fig. 11). According to the literature data, one of the most advanced thiazolidinones is D155931 and its ester D157070, selective killing nonreplicating Mycobacteria (66). Unfortunately, no literature data are available about preclinical or clinical trials of this class of potential active antimycobacterial compounds. A combinatorial library of 67 238 analogues was made based on the ethylene-diamine core of ethambutol, and many chemical libraries having a ethylene-diamine scaffold were generated using a novel synthetic approach (67–69). SQ109 is a novel ethambutol analogue (Fig. 12). Remarkably, SQ109 Fig. 11. The most active derivatives of thiazolidinones against Mycobacterium tuberculosis turned out to be a very efficient antimycobacterial, also effective against MDR strains. SQ109 is particularly active against M. tuberculosis (0.25–5 μg/ mL), M. bovis (0.25 μg/mL), and M. marinum (8 μg/mL) (68), but less active against M. avium and M. smegmatis (69). Clinical studies of SQ109 started in 2007. In 2004, Andries et al. first described the work done by Johnson & Johnson in the research and development of TMC207 (Fig. 13) (70). TMC207 is a first-in-class diarylquinone. The compound, identified by screening against M. smegmatis, has a unique mechanism of action targeting the c subunit of ATP synthase (47). It has in vitro activity against MTB H37Rv (0.06 μg/mL). TMC appears to be specific for Mycobacterium, particularly against M. tuberculosis, M. bovis, M. avium, M. kansasii, and M. smegmatis (71). In fact, 20 molecules in series of diarylquinone have a MIC below 0.5 μg/mL. The most active compound TMC207 (Tibotec) is being currently investigated in human clinical trials. Concluding remarks Over the last 40 years, no new classes of antitubercular drugs have been developed and introduced in practice; moreover, multidrug-resistant and ex- Medicina (Kaunas) 2011;47(Suppl 2) Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius 46 TMC207 1,2-Ethylenediamine Derivative Fig. 12. The most active compound of ethylenediamine derivatives against Mycobacterium tuberculosis Fig. 13. The most active compound of diarylquinone derivatives against Mycobacterium tuberculosis tensively drug-resistant Mycobacteria complicate the treatment and control of the disease across the globe. The tubercle bacillus is an astonishing microorganism, but also the biggest enemy associated with drug-resistance. The search for new antituber- cular active molecules brings challenges and opportunities for the science to defeat an old disease. Statement of Conflict of Interest The authors state no conflict of interest. Prieštuberkuliozinių junginių struktūros ir aktyvumo sąsaja Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius Lietuvos sveikatos mokslų universiteto Medicinos akademijos Vaistų chemijos katedra Raktažodžiai: tuberkuliozė, Mycobacterium tuberculosis, prieštuberkulioziniai vaistai. Santrauka. Tuberkuliozė, sukelta Mycobacterium tuberculosis, yra pirmaujanti mirties priežastis visame pasaulyje XXI amžiuje. Daugiau kaip prieš 50 metų klinikinėje praktikoje pradėta taikyti keleto vaistų terapija pacientų, užsikrėtusių tuberkulioze, gydymui, sąlygojo naujų rezistentiškų formų atsiradimą. Dėl ŽIV sinergizmo su šia liga vis blogėjanti situacija lemia didelį paplitimą ir mirtingumą. Dėl atsparių padermių didėja neveiksmingų prieštuberkuliozinių vaistų kiekis ir, deja, dauguma vaistų, kurie dabar vartojami tuberkuliozei gydyti, buvo sukurti prieš 40 metų ar daugiau, todėl šia infekcine liga pastarąjį dešimtmetį mokslininkai susidomėjo iš naujo. Šiame straipsnyje trumpai aptariami prieštuberkulioziniai vaistai, kurie dabar vartojami klinikinėje praktikoje, bei naujausi vaistų junginiai, su kuriais atliekami ikiklinikiniai ir klinikiniai tyrimai, įvertinant trumpą jų veikimo mechanizmą, susijusį su biocheminių taikinių sąveika. References 1. 2011 Global Tuberculosis Control Report, World Health Organization. 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