RESUMO
Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.
Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/ultraestrutura , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/ultraestrutura , Adamantano/análogos & derivados , Adamantano/metabolismo , Antituberculosos/química , Transporte Biológico , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Etilenodiaminas/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/ultraestrutura , Compostos de Fenilureia/metabolismo , Rimonabanto/metabolismo , Tuberculose/microbiologiaRESUMO
Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is â¼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.
Assuntos
Antituberculosos/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/farmacologia , Tuberculose/microbiologia , Animais , Antituberculosos/química , Benzofuranos/química , Benzofuranos/farmacocinética , Linhagem Celular , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacocinética , Organismos Livres de Patógenos EspecíficosRESUMO
Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.
Assuntos
Antituberculosos , Diarilquinolinas , Imidazóis , ATPases Mitocondriais Próton-Translocadoras , Mycobacterium tuberculosis , Piperidinas , Piridinas , Humanos , Antituberculosos/farmacologia , Antituberculosos/química , Sítios de Ligação , Microscopia Crioeletrônica , Diarilquinolinas/química , Diarilquinolinas/farmacologia , Imidazóis/química , Imidazóis/farmacologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , ATPases Mitocondriais Próton-Translocadoras/química , ATPases Mitocondriais Próton-Translocadoras/metabolismo , ATPases Mitocondriais Próton-Translocadoras/ultraestrutura , Modelos Moleculares , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologia , Subunidades Proteicas/metabolismo , Subunidades Proteicas/química , Subunidades Proteicas/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologiaRESUMO
Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ-876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton-conducting channel. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria.
Assuntos
Diarilquinolinas , Mycobacterium tuberculosis , Diarilquinolinas/farmacologia , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/metabolismo , Trifosfato de Adenosina/metabolismo , Mycobacterium tuberculosis/genéticaRESUMO
Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics1. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics2. Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis3. This drug can sterilize even latent M. tuberculosis infections4 and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis1,5,6. Bedaquiline targets the mycobacterial ATP synthase3, which is an essential enzyme in the obligate aerobic Mycobacterium genus3,7, but how it binds the intact enzyme is unknown. Here we determined cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in complex with bedaquiline. The drug-free structure suggests that hook-like extensions from the α-subunits prevent the enzyme from running in reverse, inhibiting ATP hydrolysis and preserving energy in hypoxic conditions. Bedaquiline binding induces large conformational changes in the ATP synthase, creating tight binding pockets at the interface of subunits a and c that explain the potency of this drug as an antibiotic for tuberculosis.
Assuntos
Complexos de ATP Sintetase/química , Antituberculosos/química , Microscopia Crioeletrônica , Diarilquinolinas/química , Mycobacterium smegmatis/enzimologia , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Complexos de ATP Sintetase/antagonistas & inibidores , Complexos de ATP Sintetase/metabolismo , Trifosfato de Adenosina/metabolismo , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Diarilquinolinas/metabolismo , Diarilquinolinas/farmacologia , Hidrólise/efeitos dos fármacos , Modelos Moleculares , Mycobacterium smegmatis/efeitos dos fármacos , RotaçãoRESUMO
The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation. This study utilizes a novel integration of computational techniques, including multiscale biomolecular and molecular dynamics simulations, physicochemical and medicinal chemistry predictions, quantum computations and virtual screening from the ZINC and Chembridge databases, to elucidate the resistance mechanism and identify lead compounds that have the potential to improve treatment outcomes for PZA-resistant MTB, namely ZINC15913786, ZINC20735155, Chem10269711, Chem10279789 and Chem10295790. These computational methods offer a cost-effective, rapid alternative to traditional drug trials by bypassing the need for organic subjects while providing highly accurate insight into the binding sites and efficacy of new drug candidates. The need for rapid and appropriate drug development emphasizes the need for robust computational analysis to justify further validation through in vitro and in vivo experiments.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Humanos , Pirazinamida/química , Pirazinamida/metabolismo , Pirazinamida/farmacologia , Mycobacterium tuberculosis/genética , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Tuberculose/microbiologia , Mutação , Testes de Sensibilidade MicrobianaRESUMO
Tuberculosis (TB) is a chronic disease caused byMycobacterium tuberculosis (Mtb), which shows a long treatment cycle often leads to drug resistance, making treatment more difficult. Immunogens present in the pathogen's cell membrane can stimulate endogenous immune responses. Therefore, an effective lipid-based vaccine or drug delivery vehicle formulated from the pathogen's cell membrane can improve treatment outcomes. Herein, we extracted and characterized lipids fromMycobacterium smegmatis, and the extracts contained lipids belonging to numerous lipid classes and compounds typically found associated with mycobacteria. The extracted lipids were used to formulate biomimetic lipid reconstituted nanoparticles (LrNs) and LrNs-coated poly(lactic-co-glycolic acid) nanoparticles (PLGA-LrNs). Physiochemical characterization and results of morphology suggested that PLGA-LrNs exhibited enhanced stability compared with LrNs. And both of these two types of nanoparticles inhibited the growth of M. smegmatis. After loading different drugs, PLGA-LrNs containing berberine or coptisine strongly and synergistically prevented the growth of M. smegmatis. Altogether, the bacterial membrane lipids we extracted with antibacterial activity can be used as nanocarrier coating for synergistic antibacterial treatment of M. smegmatisâan alternative model of Mtb, which is expected as a novel therapeutic system for TB treatment.
Assuntos
Mycobacterium smegmatis , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nanopartículas/química , Mycobacterium smegmatis/efeitos dos fármacos , Lipídeos/química , Sinergismo Farmacológico , Membrana Celular/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/administração & dosagem , Mycobacterium/efeitos dos fármacos , Berberina/farmacologia , Berberina/química , Portadores de Fármacos/química , Tuberculose/tratamento farmacológicoRESUMO
Sensing and response to environmental cues, such as pH and chloride (Cl-), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl- levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure-activity relationship studies on the hit compound "C6," or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, demonstrated a correlation between compound perturbation of Mtb Cl- response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Subsequent examination of the Cl- response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl--responsive genes in the simultaneous presence of cholesterol and high external Cl- concentration, versus transcript levels observed during exposure to high external Cl- concentration alone. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism and be exploited in antitubercular drug discovery.
Assuntos
Antituberculosos/farmacologia , Desenvolvimento de Medicamentos , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/química , Cloretos/metabolismo , Colesterol/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Macrófagos/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
Over the past 2000 years, tuberculosis (TB) has been responsible for more deaths than any other infectious disease. In recent years, there has been a recovery of research and development (R&D) efforts focused on TB drugs. This is driven by the pressing need to combat the global spread of the disease and develop improved therapies for both drug-sensitive and drug-resistant strains. Many new TB drug candidates have recently entered clinical trials, marking the beginning of a rebirth in this area after decades of neglect. The problem is that very few of the hundreds of compounds identified each year as potential anti-TB drugs really make it to the clinical development stage. This perspective focuses on the primary obstacles and approaches involved in the development of new medications for TB. This will help medicinal chemists better understand TB drug challenges and develop novel drug candidates.
Assuntos
Antituberculosos , Descoberta de Drogas , Mycobacterium tuberculosis , Tuberculose , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/síntese química , Humanos , Tuberculose/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
In a quest to discover new antimalarial and antitubercular drugs, we have designed and synthesized a series of novel triazole-quinazolinone hybrids. The in vitro screening of the triazole-quinazolinone hybrid entities against the plasmodium species P. falciparum offered potent antimalarial molecules 6c, 6d, 6f, 6g, 6j & 6k owing comparable activity to the reference drugs. Furthermore, the target compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv strain. Among the screened compounds, 6c, 6d and 6l were found to be the most active molecules with a MIC values of 19.57-40.68 µM. The cytotoxicity of the most active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed. The computational study including drug likeness and ADMET profiling, DFT, and molecular docking study was done to explore the features of target molecules. The compounds 6a, 6g, and 6k exhibited highest binding affinity of -10.3 kcal/mol with docked molecular targets from M. tuberculosis. Molecular docking study indicates that all the molecules are binding to the falcipain 2 protease (PDB: 6SSZ) of the P. falciparum. Our findings indicated that these new triazole-quinazolinone hybrids may be considered hit molecules for further optimization studies.
Assuntos
Antimaláricos , Antituberculosos , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis , Plasmodium falciparum , Quinazolinonas , Triazóis , Antituberculosos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Antimaláricos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinazolinonas/química , Quinazolinonas/farmacologia , Quinazolinonas/síntese química , Camundongos , Relação Estrutura-Atividade , Animais , Estrutura Molecular , Relação Dose-Resposta a Droga , Células RAW 264.7RESUMO
Discovered in the 1920s, cytochrome bd is a terminal oxidase that has received renewed attention as a drug target since its atomic structure was first determined in 2016. Only found in prokaryotes, we study it here as a drug target for Mycobacterium tuberculosis (Mtb). Most previous drug discovery efforts toward cytochrome bd have involved analogues of the canonical substrate quinone, known as Aurachin D. Here, we report six new cytochrome bd inhibitor scaffolds determined from a computational screen and confirmed on target activity through in vitro testing. These scaffolds provide new avenues for lead optimization toward Mtb therapeutics.
Assuntos
Antituberculosos , Inibidores Enzimáticos , Mycobacterium tuberculosis , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacologia , Antituberculosos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Tuberculose/tratamento farmacológico , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Oxirredutases/química , Modelos Moleculares , Simulação de Acoplamento MolecularRESUMO
Mycobacterium tuberculosis is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. M. tuberculosis DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit M. tuberculosis GyrB ATPase activity from the Specs compound library. This approach yielded six compounds: four carbazole derivatives (1, 2, 3, and 8), the benzoindole derivative 11, and the indole derivative 14. Carbazole derivatives can be considered a new scaffold for M. tuberculosis DNA gyrase ATPase inhibitors. IC50 values of compounds 8, 11, and 14 (0.26, 0.56, and 0.08 µM, respectively) for inhibition of M. tuberculosis DNA gyrase ATPase activity are 5-fold, 2-fold, and 16-fold better than the known DNA gyrase ATPase inhibitor novobiocin. MIC values of these compounds against growth of M. tuberculosis H37Ra are 25.0, 3.1, and 6.2 µg/mL, respectively, superior to novobiocin (MIC > 100.0 µg/mL). Molecular dynamics simulations of models of docked GyrB:inhibitor complexes suggest that hydrogen bond interactions with GyrB Asp79 are crucial for high-affinity binding of compounds 8, 11, and 14 to M. tuberculosis GyrB for inhibition of ATPase activity. These data demonstrate that virtual screening can identify known and new scaffolds that inhibit both M. tuberculosis DNA gyrase ATPase activity in vitro and growth of M. tuberculosis bacteria.
Assuntos
Antituberculosos , DNA Girase , Avaliação Pré-Clínica de Medicamentos , Indóis , Mycobacterium tuberculosis , Inibidores da Topoisomerase II , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/química , DNA Girase/metabolismo , DNA Girase/química , Ligantes , Indóis/farmacologia , Indóis/química , Antituberculosos/farmacologia , Antituberculosos/química , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Simulação de Acoplamento Molecular , Descoberta de Drogas , Testes de Sensibilidade MicrobianaRESUMO
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches. In this context, computational techniques were used to elucidate the potential molecular target underlying the inhibitory action of LQM495. Then, a consensus reverse docking (CRD) protocol was used to investigate the interactions between this compound and several Mtb targets. Out of 98 Mtb targets investigated, the enhanced intracellular survival (Eis) protein emerged as a target for LQM495. To gain insights into the stability of the LQM495-Eis complex, molecular dynamics (MD) simulations were conducted over a 400 ns trajectory. Further insights into its binding modes within the Eis binding site were obtained through a Quantum mechanics (QM) approach, using density functional theory (DFT), with B3LYP/D3 basis set. These calculations shed light on the electronic properties and reactivity of LQM495. Subsequently, inhibition assays and kinetic studies of the Eis activity were used to investigate the activity of LQM495. Then, an IC50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its Vmax, Km, and Ki parameters indicated that it is a competitive inhibitor. Lastly, this study presents LQM495 as a promising inhibitor of Mtb Eis protein, which could be further explored for developing novel anti-TB drugs in the future.
Assuntos
Antituberculosos , Proteínas de Bactérias , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Antituberculosos/farmacologia , Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Acetiltransferases/antagonistas & inibidores , Acetiltransferases/metabolismo , Relação Dose-Resposta a Droga , Simulação de Dinâmica Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese químicaRESUMO
In this study, the potential of aluminum nitride (h-AlN), boron nitride (h-BN) and silicon carbide (h-SiC) nanosheets as the drug delivery systems (DDS) of isoniazid (INH) was scrutinized through density functional theory (DFT) and molecular dynamic (MD) simulations. We performed DFT periodic calculations on the geometry and electronic features of nanosheets adsorbed with INH by the DFT functional (DZP/GGA-PBE) employed in the SIESTA code. In the energetically favorable model, an oxygen atom of the C-O group of the INH molecule interacts with a Si atom of the h-SiC at 2.077 Å with an interaction energy of -1.361 eV. Charge transfer (CT) calculation by employing the Mulliken, Hirshfeld and Voronoi approaches reveals that the monolayers and drug molecules act as donors and acceptors, respectively. The density of states (DOS) calculations indicate that the HOMO-LUMO energy gap (HLG) of the h-SiC nanosheet declines significantly from 2.543 to 1.492 eV upon the adsorption of the INH molecule, which causes an electrical conductivity increase and then produces an electrical signal. The signal is linked to the existence of INH, demonstrating that h-SiC may be an appropriate sensor for INH sensing. The decrease in HLG for the interaction of INH and h-SiC is the uppermost (up to 41%) representing the uppermost sensitivity, whereas the sensitivity trend is σ(h-SiC) > σ(h-AlN) > σ(h-BN). Quantum theory of atoms in molecules (QTAIM) investigations is employed to scrutinize the nature of the INH/nanosheet interactions. The QTAIM analysis reveals that the interaction of the INH molecule and h-SiC has a partially covalent nature, while INH/h-AlN model electrostatic interaction occurs in the system and noncovalent and electrostatic interaction for the INH/h-BN model. Finally, the state-of-the-art DFT-MD simulations utilized in this study can mimic ambient conditions. The results obtained from the MD simulation show that it takes more time to bond the INH drug and h-SiC, and the INH/h-SiC system becomes stable. The results of the current research demonstrate the potential of h-SiC as a suitable sensor and drug delivery platform for INH drugs to remedy tuberculosis.
Assuntos
Compostos de Boro , Compostos Inorgânicos de Carbono , Teoria da Densidade Funcional , Isoniazida , Simulação de Dinâmica Molecular , Compostos de Silício , Isoniazida/química , Compostos de Silício/química , Compostos Inorgânicos de Carbono/química , Compostos de Boro/química , Sistemas de Liberação de Medicamentos , Nanoestruturas/química , Antituberculosos/química , Compostos de Nitrogênio/química , Portadores de Fármacos/química , Compostos de AlumínioRESUMO
Tuberculosis (TB) treatment becomes challenging due to the unique cell wall structure of Mycobacterium tuberculosis (M. tb). Among various components of the M.tb cell wall, mycolic acid (MA) is of particular interest because it is speculated to exhibit extremely low permeability for most of the drug molecules, thus helping M.tb to survive against medical treatment. However, no quantitative assessment of the thermodynamic barrier encountered by various well-known TB drugs in the mycolic acid monolayer has been performed so far using computational tools. On this premise, our present work aims to probe the permeability of some first and second line TB drugs, namely ethambutol, ethionamide, and isoniazid, through the modelled mycolic acid monolayer, using molecular dynamics (MD) simulation with two sets of force field (FF) parameters, namely GROMOS 54A7-ATB (GROMOS) and CHARMM36 (CHARMM) FFs. Our findings indicate that both FFs provide consistent results in terms of the mode of drug-monolayer interactions but significantly differ in the drug permeability through the monolayer. The mycolic acid monolayer generally exhibited a higher free energy barrier of crossing with CHARMM FF, while with GROMOS FF, better stability of drug molecules on the monolayer surface was observed, which can be attributed to the greater electrostatic potential at the monolayer-water interface, found for the later. Although both the FF parameters predicted the highest resistance against ethambutol (permeability values of 8.40 × 10-34 cm s-1 and 9.61 × 10-31 cm s-1 for the CHARMM FF and the GROMOS FF, respectively), results obtained using GROMOS were found to be consistent with the water solubility of drugs, suggesting it to be a slightly better FF for modelling drug-mycolic acid interactions. Therefore, this study enhances our understanding of TB drug permeability and highlights the potential of the GROMOS FF in simulating drug-mycolic acid interactions.
Assuntos
Antituberculosos , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis , Ácidos Micólicos , Permeabilidade , Ácidos Micólicos/química , Ácidos Micólicos/metabolismo , Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Termodinâmica , Isoniazida/química , Etionamida/química , Etionamida/metabolismo , Etambutol/químicaRESUMO
Joining the global effort to eradicate tuberculosis, one of the deadliest infectious killers in the world, we disclose in this paper the design and synthesis of new indolinone-tethered benzothiophene hybrids 6a-i and 7a-i as potential anti-tubercular agents. The MICs were determined in vitro for the synthesized compounds against the sensitive M. tuberculosis strain ATCC 25177. Potent compounds 6b, 6d, 6f, 6h, 7a, 7b, 7d, 7f, 7h and 7i were furtherly assessed versus resistant MDR-TB and XDR-TB. Structure activity relationship investigation of the synthesized compounds was illustrated, accordingly. Superlative potency was unveiled for compound 6h (MIC = 0.48, 1.95 and 7.81 µg/mL for ATCC 25177 sensitive TB strain, resistant MDR-TB and XDR-TB, respectively). Moreover, validated in vivo pharmacokinetic study was performed for the most potent derivative 6h revealing superior pharmacokinetic profile over the reference drug. For further exploration of the anti-tubercular mechanism of action, molecular docking was carried out for the former compound in DprE1 active site as one of the important biological targets of TB. The binding mode and the docking score uncovered exceptional binding when compared to the co-crystallized ligand suggesting that it maybe the underlying target for its outstanding anti-tubercular potency.
Assuntos
Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Tiofenos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/química , Simulação de Acoplamento Molecular , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Relação Estrutura-Atividade , Testes de Sensibilidade MicrobianaRESUMO
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA.
Assuntos
Antituberculosos , Imidazóis , Mycobacterium tuberculosis , Sulfonamidas , Tiofenos , Humanos , Antituberculosos/farmacologia , Antituberculosos/química , Éter , Éteres , Sítios de Ligação , Etil-Éteres , Proteínas de Bactérias/metabolismoRESUMO
Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.
Assuntos
Isatina , Mycobacterium tuberculosis , Quinolinas , Humanos , Proteína de Transporte de Acila/farmacologia , Isatina/farmacologia , Simulação de Acoplamento Molecular , Oxirredutases/metabolismo , Antituberculosos/farmacologia , Antituberculosos/química , Testes de Sensibilidade Microbiana , Quinolinas/farmacologia , Proteínas de Bactérias/metabolismoRESUMO
Tuberculosis (TB) continues to pose a grave threat to global health, despite relentless eradication efforts. In 1882, Robert Koch discovered that Mycobacterium tuberculosis (Mtb) is the bacterium responsible for causing tuberculosis. It is a fact that tuberculosis has claimed the lives of more than one billion people in the last few decades. It is imperative that we must take immediate and effective action to increase resources for TB research and treatment. Effective TB treatments demand an extensive investment of both time and finances, often requiring 6-9 months of rigorous antibiotic therapy. The most efficient way to control tuberculosis is by receiving a childhood Bacillus Calmette-Guérin (BCG) vaccination. Despite years of research on vaccine development, we still do not have any new approved vaccine for tuberculosis, except BCG, which is partially effective in young children. This review discusses briefly the available treatment for tuberculosis and remarkable advancements in glycoconjugate-based TB vaccine developments in recent years (2013-2024) and offers valuable direction for future research priorities.
Assuntos
Antituberculosos , Glicoconjugados , Mycobacterium tuberculosis , Tuberculose , Humanos , Tuberculose/prevenção & controle , Tuberculose/tratamento farmacológico , Glicoconjugados/química , Glicoconjugados/síntese química , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Vacinas contra a Tuberculose/uso terapêutico , Desenvolvimento de Vacinas , Estrutura Molecular , AnimaisRESUMO
Tuberculosis is a global serious problem that imposes major health, economic and social challenges worldwide. The search for new antitubercular drugs is extremely important which could be achieved via inhibition of different druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) enzyme is essential for the survival of M. tuberculosis. In this investigation, a series of coumarin based thiazole derivatives was synthesized relying on a molecular hybridization approach and was assessed against thewild typeMtb H37Rv and its mutant strain (ΔkatG) via inhibiting InhA enzyme. Among the synthesized derivatives, compounds 2b, 3i and 3j were the most potent against wild type M. tuberculosis with MIC values ranging from 6 to 8 µg/ mL and displayed low cytotoxicity towards mouse fibroblasts at concentrations 8-13 times higher than the MIC values. The three hybrids could also inhibit the growth of ΔkatGmutant strain which is resistant to isoniazid (INH). Compounds 2b and 3j were able to inhibit the growth of mycobacteria inside human macrophages, indicating their ability to penetrate human professional phagocytes. The two derivatives significantly suppress mycobacterial biofilm formation by 10-15 %. The promising target compounds were also assessed for their inhibitory effect against InhA and showed potent effectiveness with IC50 values of 0.737 and 1.494 µM, respectively. Molecular docking studies revealed that the tested compounds occupied the active site of InhA in contact with the NAD+ molecule. The 4-phenylcoumarin aromatic system showed binding interactions within the hydrophobic pocket of the active site. Furthermore, H-bond formation and π -π stacking interactions were also recorded for the promising derivatives.