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BACKGROUND: Tuberculosis (TB) is the leading cause of mortality by an infectious disease worldwide. Despite national and international efforts, the world is not on track to end TB by 2030. Antibiotic treatment of TB is longer than for most infectious diseases and is complicated by frequent adverse events. To counter emerging Mycobacterium tuberculosis drug resistance and provide effective, safe drug treatments of shorter duration, novel anti-TB medicines, and treatment regimens are needed. Through a joint global effort, more candidate medicines are in the clinical phases of drug development than ever before. OBJECTIVES: To review anti-TB medicines and treatment regimens under clinical evaluation for the future treatment of drug-susceptible and drug-resistant TB. SOURCES: Pre-clinical and clinical studies on novel anti-TB drugs. CONTENT: Description of novel protein synthesis inhibitors (oxazolidinones and oxaboroles), respiratory chain inhibitors (diarylquinolines and cytochrome bc1 complex inhibitor), cell wall inhibitors (decaprenylphosphoryl-ß-d-ribose 2'-epimerase, inhibitors, thioamides, and carbapenems), and cholesterol metabolism inhibitor currently evaluated in clinical trials and novel clinical trial platforms for the evaluation of treatment regimens, rather than single entities. IMPLICATIONS: A large number of potential anti-TB candidate medicines and innovations in clinical trial design for the evaluation of regimens, rather than single medicines, provide hope for improvements in the treatment of TB.
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Antituberculosos , Mycobacterium tuberculosis , Tuberculosis , Antituberculosos/uso terapéutico , Antituberculosos/farmacología , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.
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Mycobacterium tuberculosis , Nitroimidazoles , Oxazolidinonas , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Animales , Ratones , Diarilquinolinas/farmacología , Diarilquinolinas/uso terapéutico , Antituberculosos/uso terapéutico , Antituberculosos/farmacología , Linezolid/farmacología , Linezolid/uso terapéutico , Tuberculosis/tratamiento farmacológico , Nitroimidazoles/farmacología , Oxazolidinonas/farmacología , Oxazolidinonas/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
The combination of the ß-lactam tebipenem and the ß-lactamase inhibitor avibactam shows potent bactericidal activity against Mycobacterium abscessus in vitro. Here, we report that the combination of the respective oral prodrugs tebipenem-pivoxil and avibactam ARX-1796 showed efficacy in a mouse model of M. abscessus lung infection. The results suggest that tebipenem-avibactam presents an attractive oral drug candidate pair for the treatment of M. abscessus pulmonary disease and could inform the design of clinical trials.
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Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Modelos Animales de Enfermedad , Pulmón , Pruebas de Sensibilidad MicrobianaRESUMEN
Global infections by non-tuberculous mycobacteria (NTM) are steadily rising. New drugs are needed to treat NTM infections, but the NTM drug pipeline remains poorly populated and focused on repurposing or reformulating approved antibiotics. We sought to accelerate de novo NTM drug discovery by testing advanced compounds with established activity against Mycobacterium tuberculosis 3-aminomethyl 4-halogen benzoxaboroles, a novel class of leucyl-tRNA synthetase inhibitors, were recently discovered as active against M. tuberculosis Here, we report that the benzoxaborole EC/11770 is not only a potent anti-tubercular agent but is active against the M. abscessus and M. avium complexes. Focusing on M. abscessus, which causes the most difficult-to-cure NTM disease, we show that EC/11770 retained potency against drug-tolerant biofilms in vitro and was effective in a mouse lung infection model. Resistant mutant selection experiments showed a low frequency of resistance and confirmed leucyl-tRNA synthetase as the target. This work establishes the benzoxaborole EC/11770 as a novel preclinical candidate for the treatment of NTM lung disease and tuberculosis and validates leucyl-tRNA synthetase as an attractive target for the development of broad-spectrum anti-mycobacterials.
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BACKGROUND: Although tuberculosis (TB) is a curable disease, treatment is complex and prolonged, requiring considerable commitment from patients. This study aimed to understand the common perspectives of TB patients across Brazil, Russia, India, China, and South Africa throughout their disease journey, including the emotional, psychological, and practical challenges that patients and their families face. METHODS: This qualitative market research study was conducted between July 2020 and February 2021. Eight TB patients from each country (n = 40) completed health questionnaires, video/telephone interviews, and diaries regarding their experiences of TB. Additionally, 52 household members were interviewed. Patients at different stages of their TB treatment journey, from a range of socioeconomic groups, with or without TB risk factors were sought. Anonymized data underwent triangulation and thematic analysis by iterative coding of statements. RESULTS: The sample included 23 men and 17 women aged 13-60 years old, with risk factors for TB reported by 23/40 patients. Although patients were from different countries and cultural backgrounds, experiencing diverse health system contexts, five themes emerged as common across the sample. 1) Economic hardship from loss of income and medical/travel expenses. 2) Widespread stigma, delaying presentation and deeply affecting patients' emotional wellbeing. 3) TB and HIV co-infection was particularly challenging, but increased TB awareness and accelerated diagnosis. 4) Disruption to family life strained relationships and increased patients' feelings of isolation and loneliness. 5) The COVID-19 pandemic made it easier for TB patients to keep their condition private, but disrupted access to services. CONCLUSIONS: Despite disparate cultural, socio-economic, and systemic contexts across countries, TB patients experience common challenges. A robust examination of the needs of individual patients and their families is required to improve the patient experience, encourage adherence, and promote cure, given the limitations of current treatment.
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COVID-19 , Coinfección , Tuberculosis , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Investigación Cualitativa , Tuberculosis/epidemiología , Tuberculosis/terapia , Adulto JovenRESUMEN
The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.
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Mycobacterium tuberculosis , Profármacos , Tuberculosis , Animales , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Etionamida/química , Etionamida/farmacología , Etionamida/uso terapéutico , Ratones , Profármacos/farmacología , Profármacos/uso terapéutico , Tuberculosis/tratamiento farmacológicoRESUMEN
Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen â¼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.
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COVID-19 , Mycobacterium tuberculosis , Animales , Industria Farmacéutica , Ratones , SARS-CoV-2 , Universidades , beta-Lactamas/farmacologíaRESUMEN
Fluoroquinolones-the only clinically used DNA gyrase inhibitors-are effective against tuberculosis (TB) but are in limited clinical use for nontuberculous mycobacteria (NTM) lung infections due to intrinsic drug resistance. We sought to test alternative DNA gyrase inhibitors for anti-NTM activity. Mycobacterium tuberculosis gyrase inhibitors (MGIs), a subclass of novel bacterial topoisomerase inhibitors (NBTIs), were recently shown to be active against the tubercle bacillus. Here, we show that the MGI EC/11716 not only has potent anti-tubercular activity but is active against M. abscessus and M. avium in vitro. Focusing on M. abscessus, which causes the most difficult to cure NTM disease, we show that EC/11716 is bactericidal, active against drug-tolerant biofilms, and efficacious in a murine model of M. abscessus lung infection. Based on resistant mutant selection experiments, we report a low frequency of resistance to EC/11716 and confirm DNA gyrase as its target. Our findings demonstrate the potential of NBTIs as anti-M. abscessus and possibly broad-spectrum anti-mycobacterial agents.
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Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Mycobacterium tuberculosis , Animales , Ratones , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Micobacterias no Tuberculosas , Tioinosina/análogos & derivados , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
Screening of a GSK-proprietary library against intracellular Mycobacterium tuberculosis identified 1, a thioalkylbenzoxazole hit. Biological profiling and mutant analysis revealed that this compound is a prodrug that is bioactivated by the mycobacterial enzyme MymA. A hit-expansion program including design, synthesis, and profiling of a defined set of analogues with optimized drug-like properties led to the identification of an emerging lead compound, displaying potency against intracellular bacteria in the low micromolar range, high in vitro solubility and permeability, and excellent microsomal stability.
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Antituberculosos/farmacología , Proteínas Bacterianas/metabolismo , Benzoxazoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxigenasas/metabolismo , Profármacos/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/metabolismo , Benzoxazoles/síntesis química , Benzoxazoles/metabolismo , Línea Celular Tumoral , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Profármacos/síntesis química , Profármacos/metabolismo , Relación Estructura-ActividadRESUMEN
In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5-49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome sequencing revealed mutations in the mmpL3 gene.
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This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0-τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0-14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.).
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Antituberculosos/farmacología , Compuestos de Boro/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Tuberculosis/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Área Bajo la Curva , Compuestos de Boro/administración & dosificación , Compuestos de Boro/efectos adversos , Compuestos de Boro/farmacocinética , Método Doble Ciego , Inhibidores Enzimáticos/farmacología , Femenino , Alimentos , Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Leucina-ARNt Ligasa/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Modelos Biológicos , Placebos , Adulto JovenRESUMEN
Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.
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Antituberculosos/química , Proteínas Bacterianas/antagonistas & inhibidores , Cumarinas/química , Animales , Antituberculosos/metabolismo , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Proteínas Bacterianas/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/metabolismo , Quinolinas/química , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
This corrects the article DOI: 10.1038/ncomms16081.
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BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MICâ¯=â¯0.15⯵M; SIâ¯=â¯133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.
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Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Pirroles/farmacología , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Células Hep G2 , Humanos , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.
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Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Descubrimiento de Drogas/métodos , Biblioteca de Genes , Mycobacterium tuberculosis/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas , Staphylococcus aureus/efectos de los fármacos , Acinetobacter baumannii/metabolismo , Evaluación Preclínica de Medicamentos , Terapia Molecular Dirigida , Mycobacterium tuberculosis/metabolismo , Staphylococcus aureus/metabolismoRESUMEN
BM635 is a small molecule endowed with outstanding anti-mycobacterial activity (minimum inhibitory concentration of 0.12µM against M. tuberculosis H37Rv) identified during a hit-to-lead campaign. Its poor aqueous solubility together with its high lipophilicity led to low exposure in vivo. Indeed, the half-life in vivo of BM635 was 1h, allowing a reasonable maximum concentration (Cmax=1.62µM) and a moderate bioavailability (46%). The present study aimed to develop salt forms of BM635 with pharmaceutically accepted hydrochloric, methanesulphonic, phosphoric, tartaric, and citric acids to overcome these drawbacks. BM635 salts (BM635-HCl, BM635-Mes, BM635-PA, BM635-TA and BM635-CA) were evaluated for physicochemical as well as biopharmaceutical attributes.
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Antibacterianos/química , Sales (Química)/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Disponibilidad Biológica , Semivida , Concentración de Iones de Hidrógeno , Mycobacterium tuberculosis/efectos de los fármacos , Solubilidad , Agua/químicaAsunto(s)
Antituberculosos/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Inhibidores de beta-Lactamasas/uso terapéutico , beta-Lactamas/uso terapéutico , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Recuento de Colonia Microbiana , Descubrimiento de Drogas , Humanos , Mycobacterium tuberculosisRESUMEN
We report here a dehydropeptidase-deficient murine model of tuberculosis (TB) infection that is able to partially uncover the efficacy of marketed broad-spectrum ß-lactam antibiotics alone and in combination. Reductions of up to 2 log CFU in the lungs of TB-infected mice after 8 days of treatment compared to untreated controls were obtained at blood drug concentrations and time above the MIC (T>MIC) below clinically achievable levels in humans. These findings provide evidence supporting the potential of ß-lactams as safe and mycobactericidal components of new combination regimens against TB with or without resistance to currently used drugs.
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Antibacterianos/farmacología , Dipeptidasas/deficiencia , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Tuberculosis/tratamiento farmacológico , beta-Lactamas/farmacología , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Proteínas Ligadas a GPI/deficiencia , Pulmón/metabolismo , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana/métodos , Mycobacterium tuberculosis/efectos de los fármacos , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Tuberculosis/metabolismo , Tuberculosis/microbiologíaRESUMEN
We have targeted the Mycobacterium tuberculosis decaprenylphosphoryl-ß-d-ribose oxidase (Mt-DprE1) for potential chemotherapeutic intervention of tuberculosis. A multicopy suppression strategy that overexpressed Mt-DprE1 in M. bovis BCG was used to profile the publically available GlaxoSmithKline antimycobacterial compound set, and one compound (GSK710) was identified that showed an 8-fold higher minimum inhibitory concentration relative to the control strain. Analogues of GSK710 show a clear relationship between whole cell potency and in vitro activity using an enzymatic assay employing recombinant Mt-DprE1, with binding affinity measured by fluorescence quenching of the flavin cofactor of the enzyme. M. bovis BCG spontaneous resistant mutants to GSK710 and a closely related analogue were isolated and sequencing of ten such mutants revealed a single point mutation at two sites, E221Q or G248S within DprE1, providing further evidence that DprE1 is the main target of these compounds. Finally, time-lapse microscopy experiments showed that exposure of M. tuberculosis to a compound of this series arrests bacterial growth rapidly followed by a slower cytolysis phase.