INTRODUCTION. Pharmacokinetics and metabolism of delamanid, a novel anti-tuberculosis drug, in animals and humans: importance of albumin metabolism in vivo. DLM has distinct mechanism of action, inhibiting methoxy- and keto-mycolic acid (MA) synthesis through the F420 coenzyme mycobacteria system and generating nitrous oxide. Clin. Safety assessments indicated that 98% of patients had at least one clinical manifestation, of which approximately 27% were serious. doi: 10.1128/aac.00509-16, Matsumoto, M., Hashizume, H., Tomishige, T., Kawasaki, M., Tsubouchi, H., Sasaki, H., et al. Three patients exhibited increased QTcF prolongation (QTcF interval of >500 ms) during treatment with DLM. Delamanid expanded access novel treatment of drug resistant tuberculosis. The anti-in ammatory effects of NSAIDs are due to the inhibition of prostaglandin by blocking the cyclooxygenase (COX)-2 enzymes [6]. Treatment options for MDR-and XDR-TB. This review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular basis of drug resistance in M. tuberculosis. doi: 10.1378/chest.08-2427. Thereafter, the DM-6705 is broken down by hydrolysis and CYP3A4 and converted to some other metabolites, which concentration raises to steady state during 610 weeks. Rep. 10:327. PLoS One 5:e15803. Interim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea. The https:// ensures that you are connecting to the This agent is cleaved into two reactive nitrogen species, including nitric oxide and nitrous acid with dual anti-TB effects via the disruption of the MA biosynthesis pathway, which is essential to the growth, survival, and disruption of the respiratory activity (Reichmuth et al., 2020). None of the fatal adverse events were considered to be related to DLM. eCollection 2023 Feb. Sci Rep. 2023 Feb 13;13(1):2540. doi: 10.1038/s41598-023-29652-3. 54:1900811. doi: 10.1183/13993003.00811-2019, Mukherjee, T., and Boshoff, H. (2011). (2018). Opin. They reported two patients with QTcF prolongation (QTcF interval 506 and 511 ms) and five cases with gastrointestinal problems during treatment with DLM. 73, 503508. By using resazurin microtiter assay (REMA), they identified four resistant isolates with MIC values of >32.0 mg/L. Agents Chemother. DLM did not show any effect on CYP1A1/2, CYP2A6, CYP2B6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at concentrations <100 mol/L (Matsumoto et al., 2006). Multi-drug resistant tuberculosis (MDR-TB) represents a major health problem worldwide. (2021). FOIA Gler and colleagues reported the results of the phase II trial (trial 204) on 481 patients infected with pulmonary MDR-TB. Recently, Dooley et al. N. Engl. Exposure to DLM, unlike a number of first-line anti-TB drugs (especially RIF), was enhanced by food, i.e., high-fat meal in particular. 3 However both drugs are associated with side-effects and are only . (2019). PLoS Med. Global Tuberculosis Report 2013. Lee et al. The European Medicines Agency conditionally approved DLM as a first-in-class bicyclic nitroimidazole, relying on promising results from phase IIb trial and with regard to medical need for treating MDR-TB (Blair and Scott, 2015; Khoshnood et al., 2021). The sputum of patients were cultured weekly in the MGIT system, and the results showed no difference in mean time to culture conversion between DLM and placebo groups. Notwithstanding the use of potent agents in varying combination treatment regimens, Mycobacterium tuberculosis (MTB) has an independent ability to resist antitubercular drugs (Li et al., 2019). 2023 Feb 21;21:1874-1884. doi: 10.1016/j.csbj.2023.02.035. Ethambutol is indicated in combination with other anti-tuberculosis drugs in the treatment of pulmonary tuberculosis. WHO Treatment Guidelines for Drug-Resistant Tuberculosis. World Health Organization. The finding of an in vitro drug susceptibility assessment of 90 clinical XDR MTB isolates in China indicated that four (4.4%) isolates increased MIC for DLM, and codon 318 mutation of fbiC gene was recognized as a novel mutation contributed to DLM resistance. Med. (2021). Substrate specificity of the deazaflavindependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles. Delamanid coadministered with antiretroviral drugs or antituberculosis drugs shows no clinically relevant drug-drug interactions in healthy subjects. Gandhi N.R., Moll A., Sturm A.W., Pawinski R., Govender T., Lalloo U., Zeller K., Andrews J., Friedland G. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. In animal (e.g., dog, rat, and mouse) models, DLM has been explored to have an oral bioavailability of 35%60% (Miyamoto et al., 2005; Lewis and Sloan, 2015). Before Unpublished data from an earlier research has portrayed that DLM has no activity against aerobic and anaerobic intestinal microflora (Liu et al., 2018). (2020). Moreover, the serum electrolytes are required to be assessed at baseline, and in patients with electrolyte disturbances, especially hypokalemia and hypocalcemia, DLM should not be administrated (Deltyba Epar Product Information, 2014). Toxicol. Chandramohan, Y., Padmanaban, V., Bethunaickan, R., Tripathy, S., Swaminathan, S., and Ranganathan, U. D. (2019). Khoshnood, S., Goudarzi, M., Taki, E., Darbandi, A., Kouhsari, E., Heidary, M., et al. Exposure in a fed state is almost three times higher than that of fasted state. The synergistic effect was exhibited against INH- and RIF-monoresistant and XDR isolates with FICI of 0.5, 0.5, and 0.24, respectively (Chandramohan et al., 2019). Consequently, in view of very limited clinical studies, further investigations are necessary to determine the synergistic combination effect of DLM on other drugs, and more in vivo surveys are required to corroborate the synergistic effect of DLM and to determine their toxicity, efficacy, and safety. Mechanisms of Action of TB Drugs Under Development Nitroimidazoles, SQ-109,, Meropenem, and Benzothiazinones act on cell wall synthesis. Ther. The mentioned enzyme can convert bicyclic nitroimidazole drugs to intermediate metabolites and desnitro form of DLM. Respir. Current regimens for TB treatment are lengthy, expensive and ineffective to emerging drug resistant strains. von Groote-Bidlingmaier, F., Patientia, R., Sanchez, E., Balanag, V. Jr., Ticona, E., Segura, P., et al. Although the full metabolic profile of DLM is unknown, this drug is seemingly converted to its primary metabolite, DM-6705, following the reaction of amino groups in serum albumin to this agent. Respir. PLoS Med. Plasma concentration time profiles of delamanid single oral dose and M1/M2 metabolites in mice (A) and rats (B). Several studies assessed the synergistic combination effect of DLM and BDQ and reached the conclusion that these drugs have a synergistic effect on INH- and RIF-monoresistant and also XDR-MTB clinical isolates (Ferlazzo et al., 2018; Pontali et al., 2018; Chandramohan et al., 2019; Olayanju et al., 2020). Pieterman, E. D., Keutzer, L., van der Meijden, A., van den Berg, S., Wang, H., Zimmerman, M. D., et al. (2018). The results showed that the coadministration of DLM with other anti-TB antibiotics has no clinically significant interactions (Mallikaarjun et al., 2016). Although the concern about hepatotoxicity of DLM is not as much as other anti-TB drugs such as RIF, INH, and PYR, it has been suggested that DLM may rarely have the potential effects on the liver. The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. J. Ferlazzo and associates observed no additive or synergistic QTc prolongation effect on BDQ-DLM regimen. However, another survey reflected that DLM affects the visceral leishmaniasis caused by Leishmania donovani (Patterson et al., 2016). The patients received DLM at a dose of 100 mg twice daily for 6 months and BDQ at a dose of 400 mg daily for 2 weeks, followed by 200 mg three times weekly for 5.5 months. Amsterdam: European Medicines Agency. Dis. Molecular targets related drug resistance mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis strains. 94, 309311. It is important to note that the addition of DLM to the therapeutic regimen of MDR- and XDR-TB patients should be based on individual evaluation, including drug susceptibility information, safety and tolerability of drug, and assessment of riskbenefit ratio. doi: 10.1002/9783527800315.ch7, Vilchze, C. (2020). doi: 10.1128/aac.02693-13, Heidary, M., Bostanabad, S. Z., Amini, S. M., Jafari, A., Nobar, M. G., Ghodousi, A., et al. implied that the MICs of DLM against NTM were greatly different (0.1 to > 100 g ml1), and DLM indicated a higher MIC against only M. kansasii (0.1 g mL1) compared with other tested NTMs (Koh, 2017). and transmitted securely. - patent granted by the Indian Patent . DLM has distinct mechanism of action, inhibiting methoxy- and keto-mycolic acid (MA) synthesis through the F420 coenzyme mycobacteria system and generating nitrous oxide. For instance, the DM-6705 metabolite has a key function in the prolongation of QTc. Rev. Experiences of introducing new drugs for drug-resistant TB at the ALERT Hospital, Addis Ababa, Ethiopia, 20172019. 10:1558. Antimicrob. Dis. (2020). 55:1901181. doi: 10.1183/13993003.01181-2019, Oye, K., Baird, L., Chia, A., Hocking, S., Hutt, P., Lee, D., et al. The analysis of adverse events in that clinical trial showed that the patients who received 100 mg of DLM had fewer adverse events than those who received 200 mg; most of the events were of similar incidence to patients who received placebo. disclosed that mutations in each of these five genes led to the low metabolizing potency of M. bovis BCG Tokyo and MTB H37Rv mutants in vitro. The results of that study indicated faster eradication (by at least 2 months) and shorter duration of clinical treatment of viable TB in the lungs of murine compared with the standard regimen, i.e., RIF (5 mg/kg), INH (10 mg/kg), ETB (100 mg/kg), and PYR (100 mg/kg) (Matsumoto et al., 2006). B. G6PD is also responsible for returning the F420 to the reduced form (Gurumurthy et al., 2012; Greening et al., 2016; Schuster Bruce et al., 2019). Chemical structure of delamanid (Szumowski and Lynch, 2015). In this respect, the WHO recommended clinicians for using these antibiotics under specific conditions and not in combination, owing to their high risk for cardiotoxicity. Annex I Summary of Product Characteristics. 2011 Jul;66(7):1417-30. doi: 10.1093/jac/dkr173. Delamanid (DLM) is a nitro-dihydro-imidazooxazole derivative utilized to treat MDR-TB. All of these genes and coenzymes are involved in the synthesis and recycling of cofactor F-420. 20:ciaa1577. The killing efficiency of DLM was similar to RIF, a reliable key antibiotic for intracellular MTB (Szumowski and Lynch, 2015). 2022 Dec 30;11(1):102. doi: 10.3390/microorganisms11010102. Mechanism of action of anti-tuberculosis drugs in Mycobacterium tuberculosis: (a) Rifampicin (b) Isoniazid (c) Pyrazinamide (d) Ethambutol (e, f, g) Aminoglycosides (Streptomycin, Kanamycin. Antimicrob. Migliori, G. B., Pontali, E., Sotgiu, G., Centis, R., DAmbrosio, L., Tiberi, S., et al. doi: 10.15252/msb.202211099. 109, 632641. Unauthorized use of these marks is strictly prohibited. Das, M., Mamnoon, F., Mansoor, H., Meneguim, A., Singh, P., Shah, I., et al. For 24 patients (aged 019 years) with fluoroquinolone (FQ)-resistant TB, a treatment regimen, including DLM and BDQ in combination and separately, was utilized between September 2014 and June 2018. (2011). It is taken by mouth. Similarly, the anti-TB drugs isoniazid (INH) and ethionamide (ETH) kill mycobacteria by converting to free radicals, which may thus contribute to the formation of MDR M. tuberculosis strains. Their results confirmed that the combination regimen is more effective than the standard regimen. The patients received the optimized background regimens (OBR) plus 100 mg (161 patients), 200 mg (160 patients), or placebo (160 patients) of DLM twice daily for 8 weeks. Lung Dis. Interim outcomes of delamanid for the treatment of MDR-and XDR-TB in South Korea. Common side effects include problems with vision, joint pain, nausea, headaches, and feeling . Clinical benefit of delamanid (OPC-67683) in the treatment of multidrug-resistant tuberculosis patients in China. Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit . Antitubercular agents work by stopping the growth of the bacteria that causes TB ( Mycobacterium tuberculosis ). This review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular basis of drug resistance in M. tuberculosis. 42, 715. Zazueta-Beltran J, Len-Sicairos C, Canizalez-Roman A. J Infect Dev Ctries. In a guinea pig model of TB, the effective administration dose of DLM daily was 100 mg/kg to kill MTB within hypoxic lesions of the lungs (Chen et al., 2017). Delamanid is not metabolized by Salmonella or human nitroreductases: a possible mechanism for the lack of mutagenicity. Thus, any mutations in this pathway result in the reduction of Mycobacterium bacilli to metabolize prodrug and low- to high-level DLM resistance. J. J. Antimicrob. In a study conducted by Pieterman et al. However, no resistance to DLM was observed in the placebo group (von Groote-Bidlingmaier et al., 2019). Chowdhury K, Ahmad R, Sinha S, Dutta S, Haque M. Cureus. Rifat, D., Li, S.-Y., Ioerger, T., Shah, K., Lanoix, J.-P., Lee, J., et al. J. Microbiol. The mechanism of activation has not yet been clearly understood as the binding interaction has not been appropriately established . In their survey, 38 HIV-negative patients with pulmonary MDR-TB assigned and received 100 or 200 mg of DLM twice daily or placebo for 8 weeks in combination with an OBR, including six anti-TB agents for MDR-TB therapy. Biosci. (2017). INSERM U1135 Centre d'Immunologie et de Maladies Infectieuses, France, CONICET Institute of Subtropical Biology (IBS), Argentina, Kelly Government Solutions, United States. 16:e1002873. Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2, 3-dihydroimidazo [2, 1-b] oxazoles. In exceptional circumstances, clinicians may be obligated to combine these drugs; for instance, when the number of effective drugs (at least four drugs for an efficient regimen or in cases with few treatment options) is insufficient, as well as in difficult-to-treat cases or in the emergence of excessive XDR-TB resistance. Risk Manag. (2016). 1). Development of new antituberculosis drugs from natural products. Discovery of delamanid for the treatment of multidrug-resistant pulmonary tuberculosis. The nucleotide sequence analysis of the other four genes related to DLM resistance showed no mutation in ddn, fgd1, fbiA, and fbiB genes. 12 Mechanism of action Infect. Agents Chemother. Singh R, Dwivedi SP, Gaharwar US, Meena R, Rajamani P, Prasad T. J Appl Microbiol. The median number of resistant drugs was 6 (Blair and Scott, 2015; Diel et al., 2015; Diel et al., 2015; Cox et al., 2018; World Health Organization, 2020; Khoshnood et al., 2021) and 5 (Blair and Scott, 2015; Cox et al., 2018; Heidary et al., 2019; Khoshnood et al., 2021) in patients with a final outcome and overall cohort, respectively. Mutations in the genes of the F420 signaling pathway of the MTBC, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, can lead to DLM resistance (Reichmuth et al., 2020). Rifamycins, Oxazolidinones and Macrolides act on DNA. Final treatment outcomes of delamanid-containing regimens in patients with MDR-/XDR-TB in South Korea. Figure 3. Based on the 2017 WHO Global TB Report, using BDQ and DLM was initiated in 89 and 54 countries, respectively (Cox et al., 2018). A ) and rats ( B ) treat MDR-TB ALERT Hospital, Addis Ababa, Ethiopia 20172019. Outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea pulmonary tuberculosis,! Novel series of optically active 6-nitro-2, 3-dihydroimidazo [ 2, 1-b ] oxazoles donovani ( Patterson et,... On cell wall synthesis treatment with DLM are only MTB ( Szumowski and,. Rats ( B ) donovani ( Patterson et al., 2019 ) resazurin assay. Result in the prolongation of QTc J Infect Dev Ctries results of the fatal adverse were!: 10.1038/s41598-023-29652-3 H. ( 2011 ) showed that the combination regimen is more effective than the standard regimen treatment... 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