New Developments in Drug Treatment
Peter D O Davies, Stephen B Gordon, Geraint Davies in Clinical Tuberculosis, 2014
The US FDA approval of bedaquiline is a milestone in the development of new anti-tuberculosis drugs [8]. Bedaquiline is highly selective for mycobacteria, but its target ATP synthase is an essential energy-generating mechanism found throughout all kingdoms of life. Modification of bedaquiline has led to compounds active against other clinically important bacteria [116,117], so it also represents the discovery of a novel class of antibiotics. It is reminiscent of the discovery of streptomycin in 1943 as part of a search for anti-tuberculosis drugs; this not only led to the first effective regimen for the treatment of tuberculosis in combination with isoniazid and para-aminosalicylic acid but also spawned a class of antibiotics, aminoglycosides [118], that have found wide therapeutic applications in infectious diseases. It is plausible that bedaquiline in combination with other new or repurposed compounds may herald the beginning of a similar era in the advancement of tuberculosis treatment last seen in the 1950s and 1960s.
New Developments in Drug Treatment
Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies in Clinical Tuberculosis, 2020
Parallel drug discovery efforts have also converged on another essential step in the complex assembly of the mycobacterial cell wall, DprE1, a flavoenzyme responsible for the epimerization of ribose to arabinose. This pathway provides a unique source of arabinose for both lipoarabinomannan and arabinogalactan, building blocks of the cell wall. The benzothiazinone compound BTZ043 was the first from this group to undergo significant development.48 After nitroreduction by DprE1, BTZ043 covalently binds to a cysteine residue within the active site of DprE1, irreversibly inactivating the enzyme.49–51 Laboratory-selected spontaneous resistant mutations have been localized to dprE1 and were uncommon, arising at a frequency of 10−8.48 Encouragingly, it has a very low MIC (2.3 nM against H37Rv) including against MDR strains.52 It is principally active against dividing organisms in line with its mode of action against the cell wall, and in short-term mouse studies (28 days of monotherapy) has activity similar to rifampicin.48 Combination studies conducted in vitro show it has synergistic activity against M. tuberculosis with bedaquiline and at least additive effects with a range of other first- and second-line anti-TB drugs.53
Recent Advances in the Utilization of Bioengineered Plant-Based Nanoparticles
Richard L. K. Glover, Daniel Nyanganyura, Rofhiwa Bridget Mulaudzi, Maluta Steven Mufamadi in Green Synthesis in Nanomedicine and Human Health, 2021
In recent times, repurposed and new drugs have shown marked improvement in the management of HIV patients with multidrug-resistant tuberculosis (Esmail et al., 2018). A typical example of such drug is bedaquiline. Bedaquiline should however not be used with efavirenz (Pandie et al., 2016). Careful monitoring nonetheless is required when bedaquiline is used with lopinavir–ritonavir (Svensson et al., 2014). Dolutegravir has no known interaction with either bedaquiline or antiretroviral therapy (WHO, 2013; Mallikaarjun et al., 2016). Recent information on drug interactions between anti-tuberculosis and antiretroviral therapy is available (USD, 2019).
A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis
Published in Expert Opinion on Drug Safety, 2019
Karen Cohen, Gary Maartens
Bedaquiline is a key addition to the armamentarium of drugs for drug-resistant tuberculosis; it improved time to sputum culture conversion and cure rates in a phase 2 randomised controlled trial (C208), and dramatically reduced mortality in a large cohort study. These findings resulted in the recent recommendation by WHO to include bedaquiline in all long treatment regimens for MDR-TB [4] despite the absence of data from phase 3 trials, which have only recently begun [37]. Widespread implementation of bedaquiline for drug-resistant tuberculosis has begun. This unusual situation of international public health policy being made with very limited controlled evidence is due to the low quality of evidence for most of the treatment regimens for drug-resistant tuberculosis and the fact that many of the drugs are very toxic.
Targeting ATP Synthase by Bedaquiline as a Therapeutic Strategy to Sensitize Ovarian Cancer to Cisplatin
Published in Nutrition and Cancer, 2023
Hongyan Zhu, Qitian Chen, Lingling Zhao, Pengchao Hu
Oxidative phosphorylation is a process that generate ATP through mitochondrial respiratory complexes I, II, III, IV and together with the F1F0 ATP synthase (complex V). Substantial evidence shows that oxidative phosphorylation is the main form of energy metabolism in some cancers, such as leukemia, ovarian cancer and renal cell carcinoma, and critically contributes to tumor progression and resistance (7–10). Specific agents targeting oxidative phosphorylation have been tested in pre-clinical and clinical settings to attenuate tumor progression, enhance chemosensitization and eradicate cancer stem cells in many cancers (5, 11). Bedaquiline is a FDA-approved antibiotic for treating pulmonary multidrug-resistant tuberculosis with the mechanism of action targeting ATP synthase and inducing energy crisis (12–14). Recent studies have revealed that bedaquiline decreased level of ATP synthase subunit, ATP5F1C in cancer cells, leading to mitochondrial respiration inhibition and ATP reduction, and subsequent growth arrest and inhibition of metastasis (15–17). Given the ability in inhibiting oxidative phosphorylation, we speculated that bedaquiline might be active against ovarian cancer. We thus systematically assessed the efficacy of bedaquiline using cell culturing and xenograft mouse models, and investigated the underlying mechanisms of bedaquiline focusing on oxidative phosphorylation.
Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Katharigatta N. Venugopala, Sandeep Chandrashekharappa, Pran Kishore Deb, Christophe Tratrat, Melendhran Pillay, Deepak Chopra, Nizar A. Al-Shar’i, Wafa Hourani, Lina A. Dahabiyeh, Pobitra Borah, Rahul D. Nagdeve, Susanta K. Nayak, Basavaraj Padmashali, Mohamed A. Morsy, Bandar E. Aldhubiab, Mahesh Attimarad, Anroop B. Nair, Nagaraja Sreeharsha, Michelyne Haroun, Sheena Shashikanth, Viresh Mohanlall, Raghuprasad Mailavaram
Several therapeutics have been approved by the US Food and Drug Administration (US-FDA) to enhance the treatment of TB. Bedaquiline (approved in late 2012 under the FDA’s accelerated review program) (Figure 1) was found to exhibit favourable anti-TB effects and promising anti-TB action against MDR and XDR-TB when combined with first-line or second-line anti-TB drugs, resulting in a shorter duration of treatment. However, bedaquiline suffered from various adverse effects such as nausea, elongation of QT interval, and drug interaction with Cytochrome P3A4 inducers and inhibitors11. Delamanid (Figure 1) was the second anti-TB agent approved by European Medicine Agency in late 2013. Nevertheless, resistant MTB strains against both bedaquiline and delamanid have recently been reported, which acquired resistance as a result of prolonged duration of therapy12,13. Pretomanid was the last drug candidate from the TB drug pipeline to be approved by the FDA in 2019 for the treatment of MDR and XDR TB (Figure 1)14,15.
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