Gler and colleagues reported the results of the phase II trial (trial 204) on 481 patients infected with pulmonary MDR-TB. Results of the same study showed that the difference in the median time for SCC between the two groups was insignificant during 6 months (von Groote-Bidlingmaier et al., 2019). Am. Improved fluoroquinolone-resistant and extensively drug-resistant tuberculosis treatment outcomes. Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2, 3-dihydroimidazo [2, 1-b] oxazoles. They attributed the detected unprecedented mutation in the fbiA gene (Glu249Lys) to high-level resistance to DLM and PTM in MTB, though no report of cross-resistance between DLM and PTM has been recorded to date (Jing et al., 2019). Safety assessments indicated that 98% of patients had at least one clinical manifestation, of which approximately 27% were serious. Emergence of new forms of totally drug-resistant tuberculosis bacilli: Super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. The qualitative analysis shows a lack of potential treatment options for priority resistant bacteria, especially for multidrug- and extensively drug-resistant Gram-negative pathogens. (2016). Rev. Int. An important quality for an antimicrobial drug is selective toxicity, meaning that it selectively kills or inhibits the growth of microbial targets while causing . 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). Multi-drug resistant tuberculosis (MDR-TB) represents a major health problem worldwide. Lancet Infect. Dis. J. Additionally, the clinical administration of DLM to patients needs to be concomitant with the establishment of a systematic and consistent drug susceptibility testing, in order to recognize the primary emergence of drug resistance and to prevent the transition of resistant isolates (Stinson et al., 2016). J. Drug resistant Mycobacterium tuberculosis in Mexico. Microbiologyopen 3, 823835. Combined treatment of drug-resistant tuberculosis with bedaquiline and delamanid: a systematic review. Tuberculosis (TB) is caused by various MTBC members such as MTB sensu stricto and M. africanum, as the main causes of TB in humans (Senghore et al., 2020). It was recommended that before the beginning and throughout the period of treatment with DLM, frequent monitoring of electrocardiograms is essential. Med. Describe the rationale for multiple drug therapy in treatment of TB. The rates of DLM baseline resistance and acquired DLM resistance in the DLM group were 0.39% (2/511 patients) and 1.17% (4/341 patients), respectively. Delamanid (DLM) normally exists as a prodrug and is activated by a nitroreductase encoded by deazaflavin (F420)-dependent nitroreductase (ddn) gene in MTBC. The 6-nitro-2,3-dihydro-imidazooxazol (C25H25F3N4O6), commercially named Deltyba, was introduced as a safe compound with in vivo and in vitro optimal performance (Sasaki et al., 2006; Matsumoto et al., 2007; Mukherjee and Boshoff, 2011; Tsubouchi et al., 2016). DLM, a high percentage (> 99%) protein bound, has an exceptional apparent volume of distribution (Oye et al., 2013; Chang and Sotgiu, 2017). Pulmonology 27, 403412. Repurposing clinically approved cephalosporins for tuberculosis therapy. 71, 32523259. Combined use of delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis: a systematic review. doi: 10.1002/9783527800315.ch7, Vilchze, C. (2020). Dis. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Current regimens for TB treatment are lengthy, expensive and ineffective to emerging drug resistant strains. 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). 36:e174. doi: 10.1128/aac.03014-15, Szumowski, J. D., and Lynch, J. Multidrug-resistant (MDR) isolates of Mycobacterium tuberculosis (MTB) remain a primary global threat to the end of tuberculosis (TB) era. PLoS Med. Delamanid (DLM) shows dose-dependent bactericidal activity in murine and guinea pig models infected by MTB (Chen et al., 2017). doi: 10.1016/S0140-6736(06)69573-1. FbiC encodes a F420-0 synthase that catalyzes the formation of the F420 precursor F420-0 (Fujiwara et al., 2018; Rifat et al., 2020). Sci. Plasma samples were then analyzed for DLM and its metabolites by liquid chromatography-tandem mass spectrometry assay. For anti-TB compounds, there are various mechanisms of interindividual PK variability and drugdrug interactions. Figure 3. (2013). Delamanid for multidrug-resistant pulmonary tuberculosis. 34, 12391243. (2016). Among the patients treated with BDQ, but not DLM, 284 (74.2%) achieved treatment success. Opin. (2016). Gler, M. T., Skripconoka, V., Sanchez-Garavito, E., Xiao, H., Cabrera-Rivero, J. L., Vargas-Vasquez, D. E., et al. Based on the fractional inhibitory concentration index (FICI), the aforesaid drugs are classified as synergistic or partially synergistic for tested strains (Matsumoto et al., 2006). The elimination of DLM is performed directly from plasma, but not urine, with a half-life of between 30 and 38 h. Its metabolization is also thought to be carried out, to a great extent, by plasma albumin. (2019). doi: 10.1007/s10096-019-03551-w, Kadura, S., King, N., Nakhoul, M., Zhu, H., Theron, G., Kser, C. U., et al. 373:1986. doi: 10.1056/nejmc1505196. They estimated that the in vitro spontaneous resistance frequencies for DLM ranged from 4.19 105 to 6.44 106 for MTB H37Rv and from 2.51 105 to 3.95 105 for M. bovis BCG Tokyo. The F420-dependent nitroreductase coded by ddn gene activates F420. J. Clin. See this image and copyright information in PMC. 2009 Apr 30;3(3):162-8. doi: 10.3855/jidc.31. doi: 10.1128/aac.00509-16, Matsumoto, M., Hashizume, H., Tomishige, T., Kawasaki, M., Tsubouchi, H., Sasaki, H., et al. Lancet Infect. doi: 10.1371/journal.pmed.0030466, Matsumoto, M., Hashizume, H., Tsubouchi, H., Sasaki, H., Itotani, M., Kuroda, H., et al. Epub 2023 Jan 27. Another mechanism includes drug transportation by P-glycoprotein, a significant efflux transporter that affects intracellular pharmacokinetics by transporting foreign substances out of the cells. Delamanid: from discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Int. 1). Drug Metab. In another investigation, a combination regimen, comprising of DLM (2.5 mg/kg), RIF (5 mg/kg), and pyrazinamide (PYR; 100 mg/kg), known as synergistic combination drugs, was employed for the treatment of mice (n = 6) (Matsumoto et al., 2006). Respir. 63:e00031. evaluated DLM susceptibility testing of 194 MTB strains recovered from patients. The rise of multi- and extensively drug-resistant Mycobacterium tuberculosis (M. tb) strains and co-infection with human immunodeficiency virus has escalated the need for new anti-M. tb drugs. Ramn-Garca, S., Ng, C., Anderson, H., Chao, J. D., Zheng, X., Pfeifer, T., et al. 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. Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis. Credit: NIAID Combination therapy with DLM and other active anti-TB agents is suggested for the prevention of acquired resistance (Diel et al., 2015). 3 However both drugs are associated with side-effects and are only . 2: Collateral drug resistance in drug-resistant variants of M. tuberculosis is mediated via diverse mechanisms. Das, M., Dalal, A., Laxmeshwar, C., Ravi, S., Mamnoon, F., Meneguim, A. C., et al. Microbiol. Antimicrob. Emergence of low-level delamanid and bedaquiline resistance during extremely drug-resistant tuberculosis treatment. Bedaquiline: current status and future perspectives. It was inserted into the anti-TB regime in the 50's which remains to (2020). Front. J. 49:1700387. Dis. Antimicrob. Bethesda, MD 20894, Web Policies doi: 10.1371/journal.pmed.1002873. Ramn-Garca, S., Del Ro, R. G., Villarejo, A. S., Sweet, G. D., Cunningham, F., Barros, D., et al. Tesema, E., Wares, F., Bedru, A., Negeri, C., Molla, Y., Gemechu, D., et al. Compared with DLM, INH, as the inhibitor of -MA synthesis, has a different strategy for impeding the cell wall synthesis (Lewis and Sloan, 2015). 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. J Antimicrob Chemother. J. Clin. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. Respir. Therefore, a QTc interval of DLM + BDQ was not more than additive. doi: 10.1080/03007995.2017.1415057. In healthy volunteers, an interaction was observed between DLM and the strong CYP3A4 enzyme inducer, RIF, which diminished exposure to DLM by 47%. Yimer, S. A., Kalayou, S., Homberset, H., Birhanu, A. G., Riaz, T., Zegeye, E. D., et al. Despite the use of a wide variety of potent antibiotics for TB, an effective treatment is a serious challenge in the TB-affected patients (Heidary and Nasiri, 2016). Lewis, J. M., and Sloan, D. J. Plasma concentration time profiles of delamanid single oral dose and M1/M2 metabolites in mice (A) and rats (B). Microbiol. Delamanid susceptibility testing of mycobacterium tuberculosis using the resazurin microtitre assay and the BACTECTM MGITTM 960 system. Kim et al., however, denoted that MTB had high MIC values against NTM, except for M. kansasii (Kim et al., 2019). A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. Lancet Infect. Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: results from a large global cohort. Antimicrob. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. Hydroxylation of the oxazole moiety of M1, the most crucial starting point, to form M2, and also consecutive oxidation to the ketone form (M3), are two main pathways in humans that are mostly performed by CYP3A4 (Figure 3) (Sasahara et al., 2015). In a multicenter study conducted from 2010 to 2019 in Korea, 633 patients with MDR-TB were analyzed. In vitro activities of bedaquiline and delamanid against nontuberculous mycobacteria isolated in Beijing, China. In that observational study, serious adverse events happened in 11.7% of the DLM-treated group, and the most prevalent adverse events reported were anemia, hemoptysis, QTc interval prolongation, and psychotic disorder (Skripconoka et al., 2013). Agents Chemother. In this respect, in vitro synergy assays have suggested strong synergistic interaction between -lactams (cephradine and faropenem) and DLM (FICI of 0.5) for MDR- and XDR-TB, which might possibly be effectual in reducing treatment length. (2020). 60, 59765985. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. Delamanid and bedaquiline resistance in Mycobacterium tuberculosis ancestral Beijing genotype causing extensively drug-resistant tuberculosis in a Tibetan refugee. (2021), the synergistic effect of combination regimen (DLM (2.5 mg/kg), BDQ (25 mg/kg), and linezolid (100 mg/kg) was compared with the standard regimen (ETB, PYR, RIF, and INH) in TB-infected mice. 2. J. Korean Med. Chemother. Drug efflux and the activity of efflux transporters likely play important roles in the development of drug-tolerant and drug-resistant mycobacterial phenotypes. 38, 12931296. However, WHO reported that the combination of moxifloxacin and DLM might increase the risk of QT prolongation (World Health Organization, 2016). Treatment with a single drug can lead to the development of a bacterial population resistant to that drug. A comparison between the DLM and placebo groups showed that the prevalence of QTc interval prolongation in patients who received DLM was significantly higher than that in the placebo group. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs. 19, 348353. Comput Struct Biotechnol J. Agents Chemother. Mycobacterium tuberculosis ancestral Beijing genotype causing extensively drug-resistant tuberculosis in vitro and in mice 960 system system! Which remains to ( 2020 ) multi-drug resistant tuberculosis ( MDR-TB ), and Sloan, D. J in... Pulmonary multidrug-resistant tuberculosis ( MDR-TB ) Korea, 633 patients with MDR-TB were analyzed patients at... 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