macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation - LARVOL DELTA

Discovery, Design, and Synthesis of Novel 2-Benzyl-2,7-diazaspiro[3.5]nonane Benzothiazinones with Broad-Spectrum Antimycobacterial Activity. (PubMed, J Med Chem) - "Despite their nanomolar potency against M. tuberculosis (MTB), benzothiazinone (BTZs) DprE1 inhibitors like PBTZ169 are ineffective against nontuberculous mycobacteria (NTM) due to a Cys387Ala mutation in the NTM DprE1 target...As this residue is highly conserved among mycobacterial species, such an interaction likely underpins its broad-spectrum activity. Therefore, our findings provide a blueprint for developing next-generation BTZs with broad-spectrum activity against mycobacteria."

Journal • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Discovery of potent DprE1-targeted antitubercular agents: synthesis and evaluation of PBTZ169/TBA7371-based derivatives. (PubMed, Mol Divers) - "Furthermore, molecular dynamics (MD) simulations confirmed the high stability of the 9m -DprE1 complex compared to the standard reference compound. These findings suggest that compound 9m  could lead to the development of novel antitubercular agents."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

An integrated computational bioprospection of flavonoids as modulators of Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose-2'-epimerase 1. (PubMed, Comput Biol Chem) - "Furthermore, commonly used TB medications like isoniazid (INH) and rifampicin (RIF) are associated with adverse side effects...Our results showed that the top five compounds exhibited more favourable binding free energy values against DprE1 than the standard, PBTZ169...These findings suggest a potential structural mechanism for the inhibitory action of cycloartobiloxanthone against Mycobacterium tuberculosis DprE1. While this study highlights the potential of cycloartobiloxanthone as a lead compound, further validation through in vivo and in vitro studies is recommended."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

TAK1 phosphorylation mediates macozinone (PBTZ169) induced innate immune activation against tuberculosis. (PubMed, mSphere) - "Current therapeutic strategies, however, predominantly focus on achieving maximal bacterial suppression within compressed timelines while overlooking the immunomodulatory consequences of anti-tuberculosis agents. This critical knowledge gap underscores the urgent need for mechanistic investigations to establish evidence-based frameworks for optimizing drug combinations and integrating therapies with host-directed approaches."

Journal • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

In-Silico Exploration of the StreptomeDB Database for Potential Irreversible DprE1 Inhibitors toward Antitubercular Treatment. (PubMed, ChemistryOpen) - "StreptomeDB compounds exhibiting covalent docking scores lower than PBTZ169, the reference inhibitor, against DprE1 (calc...Robust bioavailability and drug-likeness characteristics are expected for the investigated StreptomeDB compounds. These findings unveiled promising inhibitory activity for hydroxythaxtomin A and lajollamycin B against DprE1."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

In vitro and in vivo activities of a novel benzothiopyranone candidate NTB-3119M against Mycobacterium tuberculosis. (PubMed, Tuberculosis (Edinb)) - "Our research provided comprehensive evidence that NTB-3119M with increased water solubility and bioavailability based on previous research performed excellent anti-tuberculosis activity and less cytotoxicity, which effectively tackled the undesirable drug properties associated with previous benzothiopyrone derivatives. It is warranted that NTB-3119M, as a highly promising candidate anti tuberculosis drug, deserves further research and clinical trial."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Verapamil and its metabolite norverapamil inhibit the Mycobacterium tuberculosis MmpS5L5 efflux pump to increase bedaquiline activity. (PubMed, Proc Natl Acad Sci U S A) - "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."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

DprE1 Inhibitors: An insight into the recent developments and synthetic approaches. (PubMed, Eur J Pharm Sci) - "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 • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Annual progress of new drugs and new regimens for anti-tuberculosis treatment (2024) (PubMed, Zhonghua Jie He He Hu Xi Za Zhi) - "There are multiple new drugs in the clinical trial stage, such as macozinone, sutezoid, alpiberctin, and GSK3036656. The effectiveness, safety, and resistance issues of marketed drugs such as linezolid, bedaquiline, and delamanid are also of great concern...WHO has also updated the preventive treatment plan for people at high risk of TB. This article reviews the literature published from October 1, 2023 to September 30, 2024."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis. (PubMed, Pharmaceuticals (Basel)) - "Isoniazid, thioamides, and delamanid primarily disrupt mycolic acid synthesis, with recent evidence indicating that delamanid also inhibits decaprenylphosphoryl-β-D-ribose-2-epimerase, thereby impairing arabinogalactan biosynthesis. Furthermore, ethambutol interferes with arabinogalactan synthesis by targeting arabinosyl transferase enzymes, particularly embB- and embC-encoded variants. Beyond these, six promising molecules currently in Phase II clinical trials are designed to target arabinan synthesis pathways, sutezolid, TBA 7371, OPC-167832, SQ109, and both benzothiazinone derivatives BTZ043 and PBTZ169, highlighting advancements in the development of cell wall-targeting therapies."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Real-time evaluation of macozinone activity against Mycobacterium tuberculosis through bacterial nanomotion analysis. (PubMed, Antimicrob Agents Chemother) - "We evaluated the in vitro activity of two benzothiazinone drug candidates (MCZ, PBTZ169; BTZ043) and their main metabolites against MTB using advanced nanomotion technology. 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."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Benzothiazinone analogs as Anti-Mycobacterium tuberculosis DprE1 irreversible inhibitors: Covalent docking, validation, and molecular dynamics simulations. (PubMed, PLoS One) - "Macozinone (PBTZ169, a benzothiazinone (BTZ) derivative) is an irreversible DprE1 inhibitor that has attracted considerable attention because it exhibits an additive activity when combined with other anti-TB drugs...Physicochemical and ADMET characteristics indicated the oral bioavailability of the identified BTZ analogs. The obtained in-silico results provide promising anti-TB inhibitors that are worth being subjected to in-vitro and in-vivo investigations."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Efficacy of Macozinone and Sutezolid against Mycobacterium leprae (ASTMH 2024) - "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."

Clinical • Infectious Disease

Advances in antibacterial agents for Mycobacterium fortuitum. (PubMed, RSC Med Chem) - "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."

Journal • Review • Infectious Disease • Nontuberculous Mycobacterial Disease

Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility. (PubMed, Eur J Med Chem) - "Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H37Rv and MDR-MTB strains (MIC:  2000 μg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery."

Journal

Pharmacophore mapping, 3D QSAR, molecular docking, and ADME prediction studies of novel Benzothiazinone derivatives. (PubMed, In Silico Pharmacol) - "Clinical trial drugs such as BTZ043, BTZ038, PBTZ169, and TMC-207 have shown promising results as DprE1 inhibitors. Docking validation via RMSD values supported the reliability of the docking results. This comprehensive approach aids in the design of novel benzothiazinone derivatives with potential anti-tubercular properties, contributing to the development of novel anti-tubercular agents which can be pivotal in the eradication of tuberculosis."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Identifying Novel Therapeutics for the Resistant Mutant "F533L" in PBP3 of Pseudomonas aeruginosa Using ML Techniques. (PubMed, ACS Omega) - "Out of 8 compounds, 3 compounds, namely, macozinone, antibacterial agent 71, and antibacterial agent 123, showed good stability and were validated by RMSD, RMSF, and binding-free analysis. The findings of this study revealed promising antibacterial compounds against the F533L mutant PBP3. Furthermore, developments in these compounds may pave the way for novel therapeutic interventions."

Journal • Infectious Disease

Efficacy of Macozinone in Mice with Genetically Diverse Susceptibility to Mycobacterium tuberculosis Infection. (PubMed, Microbes Infect) - "Macozinone demonstrated efficacy to varying degrees across all mouse models of Mtb infection used. These results should facilitate its further development and potential introduction into clinical practice."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Targeting decaprenylphosphoryl-β-D-ribose 2'-epimerase for Innovative Drug Development Against Mycobacterium Tuberculosis Drug-Resistant Strains. (PubMed, Bioinform Biol Insights) - "Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Nanomotion-based rapid phenotypic approach for the screening of new drugs for the treatment of Mycobacterium tuberculosis: focus on Macozinone (ECCMID 2024) - No abstract available

Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity. (PubMed, Biomedicines) - "The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-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."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling. (PubMed, Eur J Med Chem) - "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 • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Design, synthesis and antitubercular activity of novel N-(amino)piperazinyl benzothiazinones with improved safety. (PubMed, Eur J Med Chem) - "Our results show that majority of them exhibit the same potent or comparable activity against both MTB HRv and MDR-MTB strains (MIC: 4.00 -  500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The DprE1 Inhibitors: Enduring aspirations for future Anti-TB Drug Discovery. (PubMed, ChemMedChem) - "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. Furthermore, we examine the resistance mechanisms associated with DprE1 inhibitors to understand future developments due to resistance emergence. This comprehensive review offers insights into the DprE1 active site, including protein-binding maps, PQS, and graphical representations of known inhibitors, making it a valuable resource for medicinal chemists working on future antitubercular compounds."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Efficacy of PBTZ169 and pretomanid against Mycobacterium avium, Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum in BALB/c mice models. (PubMed, Front Cell Infect Microbiol) - "The in vivo activities of bedaquiline, clofazimine, moxifloxacin, rifabutin, PBTZ169 and pretomanid against four common NTMs were assessed in murine models. PBTZ169 appears to be a candidate for treating four common NTM infections. Pretomanid was more active against M. abscessus, M. chelonae and M. fortuitum than against M. avium."

Journal • Preclinical • Infectious Disease • Nontuberculous Mycobacterial Disease • Respiratory Diseases