- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Review, Journal: DprE1 Inhibitors: An insight into the recent developments and synthetic approaches. (Pubmed Central) - May 18, 2025
DprE1 inhibitors can be categorized according to the formation of a covalent or non-covalent bond in the enzyme's active site, causing a loss of its catalytic activity, leading to Mtb's demise. Herein, we describe diverse DprE1 inhibitors that have had anti-tubercular activity reported over the past fifteen years and till the present time.
- |||||||||| Journal: Verapamil and its metabolite norverapamil inhibit the Mycobacterium tuberculosis MmpS5L5 efflux pump to increase bedaquiline activity. (Pubmed Central) - Apr 17, 2025
Here, we show that the MmpS5L5 efflux pump reduces susceptibility to bedaquiline as well as its new, more potent derivative TBAJ-876 and other antimicrobial substrates, including clofazimine and the DprE1 inhibitors PBTZ-169 and OPC-167832...Finally, norverapamil, the major verapamil metabolite, which has greatly reduced calcium channel activity, has equal potency in reducing resistance to MmpS5L5 substrates. Our findings highlight verapamil's potential for enhancing bedaquiline TB treatment, for preventing acquired resistance to bedaquiline and other MmpS5L5 substrates, while also providing the impetus to identify additional MmpS5L5 inhibitors.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Real-time evaluation of macozinone activity against Mycobacterium tuberculosis through bacterial nanomotion analysis. (Pubmed Central) - Jan 31, 2025
PBTZ169 and H2-PBTZ169 achieved 100% separation between the susceptible H37Rv and a resistant dprE1 mutant strain NTB1. These findings support nanomotion technology's potential for faster antibiotic susceptibility testing of novel MTB drug candidates targeting the DprE1 enzyme that could reduce empirical treatment duration and antibiotic resistance selection pressure due to inaccurate treatments.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Review, Journal: Advances in antibacterial agents for Mycobacterium fortuitum. (Pubmed Central) - Nov 4, 2024
Most compounds effective against M. fortuitum are synthetic, with macozinone, featuring a 2-piperazine-benzothiazinone framework, standing out as a notable drug candidate...Some compounds' mechanisms of action on M. fortuitum have been studied, including NITD-916, which acts as an enoyl-acyl carrier protein reductase inhibitor, and TBAJ-5307, which inhibits F-ATP synthase. Moreover, this review discusses the pathogenic molecular mechanisms and potential therapeutic targets within this mycobacterium.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation, Sutezolid (PNU-100480) / Sequella
Efficacy of Macozinone and Sutezolid against Mycobacterium leprae (Convention Center - Hall I-1 (1st Floor); In-Person-Only) - Oct 11, 2024 - Abstract #ASTMH2024ASTMH_2195;
Results & Conclusion Results show that Macozinone and Sutezolid are effective against M. lepra e both in vitro (axenic and intracellular) and in vivo (MFP). Therefore, Macozinone and Sutezolid, having different modes of action, should be tested in combination with other first and second line drugs to explore new shorter treatment regimens for leprosy.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity. (Pubmed Central) - Jul 29, 2023
The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-?-D-ribose 2'-oxidase (DprE1)...The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling. (Pubmed Central) - Jun 16, 2023
The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development...Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.
- |||||||||| Journal: The DprE1 Inhibitors: Enduring aspirations for future Anti-TB Drug Discovery. (Pubmed Central) - May 29, 2023
This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant. We also introduce a protein quality score (PQS) and an active-site map of the DprE1 enzyme to help medicinal chemists better understand DprE1 inhibition and develop new, effective anti-TB drugs.
- |||||||||| Review, Journal: Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones. (Pubmed Central) - Apr 19, 2023
The review covers synthesis, structures and reactivity, mechanism of action, in vitro activity and structure activity relationships (SARs), physicochemical and pharmacokinetic properties as well as a brief summary of in vivo models and clinical studies. We address bioavailability issues and the challenge of the potentially toxic nitroaromatic moiety, including reactivity towards nucleophiles in vivo and highlight possible directions of further research into BTZs through chemical modification.
- |||||||||| telacebec (Q203) / Qurient, macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Synergistic Effect of Q203 Combined with PBTZ169 against Mycobacterium tuberculosis. (Pubmed Central) - Nov 3, 2022
Zebrafish (Danio rerio)-Mycobacterium marinum infection and a curing model further validated the synergistic effect of Q203 and PBTZ169 in vivo. In this study, the synergy between these two new antituberculosis drugs, Q203 and PBTZ169, is an important finding that could lead to the development of a new TB regimen.
- |||||||||| BTZ-043 / Hans Knöll Institute, Sirturo (bedaquiline) / J&J, Pharmstandard, macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Mutations in rv0678 Confer Low-Level Resistance to Benzothiazinone DprE1 Inhibitors in Mycobacterium tuberculosis. (Pubmed Central) - Sep 24, 2022
We confirmed that rv0678 mutations from clinical isolates confer low level cross-resistance to BTZ043 and PBTZ169. While it is yet unclear whether rv0678 mutations would render benzothiazinones ineffective in treating TB, these results highlight the importance of monitoring for clinically prevalent rv0678 mutations during ongoing BTZ043 and PBTZ169 clinical trials.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Identification of Mutations Associated With Macozinone-Resistant in Mycobacterium Tuberculosis. (Pubmed Central) - Jun 4, 2022
Of low-level resistant clones other gene mutations involved in drug efflux or membrane permeability were found (pepQ, Rv0678, arsC, etc.), with highest mutation frequency in Rv0678 (50/64, 78.12%). It suggests that there may be new mechanisms independent of dprE1 mutations.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Development of 6-Methanesulfonyl-8-nitrobenzothiazinone Based Antitubercular Agents. (Pubmed Central) - Apr 23, 2022
Among these compounds, MsPBTZ169 and compounds 2 and 8 exhibited minimum inhibitory concentrations (MICs) of less than 40 nM; moreover, these compounds displayed increased aqueous solubility and acceptable metabolic stability. Taken together, this study suggested that the 6-methanesulfonyl substituted 8-nitrobenzothiazinone derivatives, in combination with side chain modification, might provide BTZ type antitubercular agents with improved drug-like properties.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents. (Pubmed Central) - Feb 16, 2022
Compared to PBTZ169, both compounds displayed increased aqueous solubility and higher stability in human liver microsomes. This study suggested that an alternative side-chain modification strategy could be implemented to improve the druglike properties of the BTZ-based compounds.
- |||||||||| rifampicin / Generic mfg.
Journal: Exploring targets of cell wall protein synthesis and overexpression mediated drug resistance for the discovery of potential M. tb inhibitors. (Pubmed Central) - Feb 8, 2022
The early detection of mycobacterium tuberculosis can be permanently cured by DOTS comprising Pyrazinamide (Z), Isoniazid (H), Rifampin (R) and Ethambutol (E)...Overexpression of these genes may produce drug-resistant due to dose misuse or the intake of quality compromised anti tubercular drug regimen. Therefore, in the present review there has been a necessity to report the second line antitubercular chemotherapeutics to target various proteins which are the building block of M. tb cell wall, overexpression of which may produce drug resistance.
- |||||||||| TBA-7371 / Bill & Melinda Gates Foundation, Global Alliance for TB Drug Development, Foundation for Neglected Disease Research, OPC-167832 / Otsuka, macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
PK/PD data, Preclinical, Journal: Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 inhibitors TBA-7371, PBTZ169 and OPC-167832. (Pubmed Central) - Nov 4, 2021
Superior efficacy was observed for OPC-167832 even at low dose levels, which can be attributed to its low MIC, favorable distribution and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.
- |||||||||| Lamprene (clofazimine) / Novartis
Review, Journal: An overview of new antitubercular drugs, drug candidates, and their targets. (Pubmed Central) - Jul 9, 2021
The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid...These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug-target interactions, and their structure-activity relationship.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones. (Pubmed Central) - Jun 22, 2021
8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis...X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents. (Pubmed Central) - May 27, 2021
Among them, the 1,3-benzothiazinone compounds such as BTZ043, and its closer congener, PBTZ169, are undergoing clinical studies...To test this hypothesis, a number of covalent inhibitors of DprE1 were designed and prepared. The compounds inhibitory potency against DprE1 and anti-tubercular activity were investigated, their chemical reactivity, formation of covalent adduct between the warhead and the enzyme was demonstrated by mass spectrometry.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic
Journal: 8-cyanobenzothiazinone analogs with potent antitubercular activity. (Pubmed Central) - Jan 20, 2021
Analysis of the C-2 substituent of 1d revealed similar structure-activity relationships as observed for macozinone. Overall, the results confirm the 8-nitro group of benzothiazinones can be successfully replaced with a nitrile to retain useful activity and favorable pharmacokinetic properties.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic
Journal: Identification of benzothiazinones containing 2-benzyl-2,7-diazaspiro[3.5]nonane moieties as new antitubercular agents. (Pubmed Central) - Oct 27, 2020
With one exception 3, all of them show excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016 μg/mL). Compound 2d with a methyl group at the benzylic carbon, was identified to have good safety and significant efficacy in an acute mouse model of TB, as well as better PK profiles than PBTZ169.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Trial completion, Trial completion date, Trial primary completion date: Study to Evaluate the Safety, Tolerability and Pharmacokinetics of PBTZ169 in Multiple Dosing (clinicaltrials.gov) - Oct 22, 2020
P1, N=32, Completed,
Compound 2d with a methyl group at the benzylic carbon, was identified to have good safety and significant efficacy in an acute mouse model of TB, as well as better PK profiles than PBTZ169. Recruiting --> Completed | Trial completion date: Oct 2019 --> Mar 2020 | Trial primary completion date: Sep 2019 --> Mar 2020
- |||||||||| clarithromycin / Generic mfg., rifampicin / Generic mfg.
Preclinical, Journal: Telacebec (Q203)-containing intermittent oral regimens sterilized mice infected with Mycobacterium ulcerans after only 16 doses. (Pubmed Central) - Oct 7, 2020
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin...The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active...Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic
Preclinical, Journal: A rapid method for estimation of the efficacy of potential antimicrobials in humans and animals by agar diffusion assay. (Pubmed Central) - May 7, 2020
We now describe a simple agar diffusion assay, which can be used as a general method for the rapid detection of antimicrobial activity of drug candidates in animal or human blood plasma for the ultimate prediction of the efficacy of potential drugs prior to clinical trials. We present an example for a clinical candidate against Mycobacterium tuberculosis.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic
Journal: Design, synthesis and antimycobacterial activity of less lipophilic Q203 derivatives containing alkaline fused ring moieties. (Pubmed Central) - Jan 17, 2020
Nine compounds (13, 15, 19, 21, 23, 25, 29, 35, 36) have the same excellent activity against both drug-sensitive and -resistant strains (MIC < 0.035 μM) as Q203 and PBTZ169. Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery.
- |||||||||| macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Enrollment open, Trial primary completion date: Study to Evaluate the Safety, Tolerability and Pharmacokinetics of PBTZ169 in Multiple Dosing (clinicaltrials.gov) - Feb 27, 2019
P1, N=32, Recruiting,
Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery. Not yet recruiting --> Recruiting | Trial primary completion date: Jun 2019 --> Sep 2019
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