ABSTRACT
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.
Subject(s)
Mycobacterium tuberculosis , Prodrugs , Tuberculosis , Animals , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Ethionamide/chemistry , Ethionamide/pharmacology , Ethionamide/therapeutic use , Mice , Prodrugs/pharmacology , Prodrugs/therapeutic use , Tuberculosis/drug therapyABSTRACT
Background: Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified Shigella spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for Shigella infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. Methods: Aiming to identify alternative antimicrobial chemicals with activity against antimicrobial resistant Shigella, we initiated a collaborative academia-industry drug discovery project, applying high-throughput phenotypic screening across broad chemical diversity and followed a lead compound through in vitro and in vivo characterisation. Results: We identified several known antimicrobial compound classes with antibacterial activity against Shigella. These compounds included the oral carbapenem Tebipenem, which was found to be highly potent against broadly susceptible Shigella and contemporary MDR variants for which we perform detailed pre-clinical testing. Additional in vitro screening demonstrated that Tebipenem had activity against a wide range of other non-Shigella enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating Tebipenem. We found the orally bioavailable prodrug (Tebipenem pivoxil) had ideal pharmacokinetic properties for treating enteric pathogens and was effective in clearing the gut of infecting organisms when administered to Shigella-infected mice and gnotobiotic piglets. Conclusions: Our data highlight the emerging antimicrobial resistance crisis and shows that Tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) should be accelerated into human trials and could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs. Funding: Tres Cantos Open Lab Foundation (projects TC239 and TC246), the Bill and Melinda Gates Foundation (grant OPP1172483) and Wellcome (215515/Z/19/Z).
Subject(s)
Anti-Infective Agents , Communicable Diseases , Shigella , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Carbapenems/pharmacology , Carbapenems/therapeutic use , Child , Diarrhea , Drug Repositioning , Humans , Mice , SwineABSTRACT
Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.
Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antimalarials/pharmacology , Oxadiazoles/pharmacology , 2,2'-Dipyridyl/administration & dosage , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacology , 2,2'-Dipyridyl/toxicity , Animals , Antimalarials/administration & dosage , Antimalarials/chemical synthesis , Antimalarials/toxicity , Atovaquone/pharmacology , Chloroquine/pharmacology , Drug Design , Female , Humans , Hydrazines/metabolism , Mice , Mutagenicity Tests , Mutagens/metabolism , Oxadiazoles/administration & dosage , Oxadiazoles/chemical synthesis , Oxadiazoles/toxicity , Parasitemia/drug therapy , Plasmodium falciparum/drug effects , Pyrimethamine/pharmacology , Structure-Activity RelationshipABSTRACT
Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue 44 displayed potent in vitro activity (IC50 = 10 nM) and oral activity in a SCID mouse model of Pf infection with an ED50 of 100 and ED90 of between 100 and 150 mg kg(-1), respectively. The results presented encourage further investigations to identify the target of these highly active compounds.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Animals , Antimalarials/metabolism , High-Throughput Screening Assays , Humans , In Vitro Techniques , Malaria/drug therapy , Malaria/psychology , Malaria, Falciparum/drug therapy , Mice , Mice, SCID , Microsomes, Liver/metabolism , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Serine Proteinase Inhibitors/metabolism , Structure-Activity Relationship , Triazoles/metabolismABSTRACT
Introducción. El hiperparatiroidismo secundario refractario a tratamiento médico es una complicación frecuente en pacientes con insuficiencia renal crónica y terapia dialítica prolongada, que obliga a intervención quirúrgica de las glándulas paratiroideas, con los riesgos y coste del procedimiento quirúrgico. Objetivo: Evaluar la efectividad terapéutica y seguridad de la ablación de adenomas paratiroideos, mediante inyección percutánea deetanol con guía ecográfica. Método: Previo consentimiento informado y aprobación por el comité de ética médica institucional, se estudiaron prospectivamente 15 pacientes que reunieron los criterios de inclusión. Utilizando guía ecográfica se inyectó etanol a adenomas paratiroideos en una o varias sesiones con intervalo menor a seismeses. Resultados: En los 15 pacientes se midió el tamaño de los adenomas, se evaluó su vascularización mediante Doppler, se determinó la concentración de paratohormona, calcio y fósforo, antes de las ablaciones y después de éstas, como criterios de respuesta altratamiento. En seis pacientes (40%) no hubo respuesta terapéutica, mientrasque en 9 pacientes se obtuvo respuesta (60%). En este último grupo, cincopacientes (33,3%) presentaron respuesta exitosa y mejoría sintomática; en dospacientes (13,3%), la respuesta terapéutica fue subóptima, y en dos pacientes (13,3%), no fue satisfactoria. No hubo complicaciones mayores. Conclusión: La ablación de adenomas paratiroideos con inyección percutánea de etanol y guía ecográfica en pacientes urémicos con hiperparatiroidismo secundario refractario a tratamiento médico es una terapia efectiva y segura. Se sugiere continuar la misma línea de investigación con estudios que involucren más pacientes y tiempos de seguimiento mayores.
Introduction: Secondary hyperparathyroidism unresponsive to medical treatment is a common complication in patients with chronic renal failure and prolonged dialysis therapy, which requires surgery of the parathyroid glands, with the risks and costs of surgery. Objective: To evaluate the therapeutic effectiveness and safety of ablation of parathyroid adenomas by percutaneous ethanol injection under ultrasound guidance. Method: After approval by the institutional medical ethics committee, informed written consent was obtained in 15 patients who met the inclusion criteria. Sonographically guided ethanol was injected consecutively into adenomas, with an interval of time less than six months. Results: Size, Doppler vascularity of adenomas, and the levels of parathyroid hormone, calcium and phosphoruswere measured before andafter ablation as criteria for treatment response in 15 patients. Of all patients,six (40%) had no therapeutic response. Therapeutic response was observedin nine patients (60%). In the latter group, five patients (33.3%) had successful response and symptomatic improvement, in two patients (13.3%), therapeutic response was suboptimal, and in two patients (13.3%), the response was unsatisfactory. The procedure was safe. Local pain, transient dysphonia and cough were considered minor complications and were the most common, with resolution in all cases. There were no major complications. Conclusion: Ablation of parathyroidadenomas with percutaneous ethanol injection andultrasound guidance, in uremicpatients with secondary hyperparathyroidismunresponsive to medical treatment is aneffective and safe therapy. Studiesinvolving more patients and longer follow up are needed in order to stablishmore conclusive results.
Subject(s)
Humans , Ablation Techniques , Ethanol , Hyperparathyroidism , Ultrasonics , UremiaABSTRACT
El estudio de la enfermedad metabólica ósea es amplio y complejo. La enfermedad ósea más reconocida por médicos de todas las especialidades es la osteoporosis, probablemente debido a su elevada frecuencia. No obstante, es importante reconocer que existen numerosas entidades que afectan el metabolismo óseo de diferentes formas, llevando a fragilidad ósea, aumento del riesgo de fractura, osteoporosis u osteocondensación, de acuerdo a cada caso particular. Tanto el diagnóstico clínico como el reconocimiento de la alteración metabólica subyacente son importantes porque la identificación de la anormalidad específica se constituye en la base para el tratamiento. Se presentan 5 casos diferentes en los que un trastorno metabólico conlleva a una patología ósea específica; se discute la patogenia de las calcificaciones arteriales y se presenta una entidad mixta que nosotros llamamos osteoporomalacia.
The study of metabolic bone disease is broad and complex. The most widely recognized bone disease by physicians of all specialties is osteoporosis, probably due to its high frequency. However, it is important to recognize that there are numerous entities that affect bone metabolism in different ways, leading to brittle bones, increased risk of fracture, osteoporosis or osteocondensation, according to each particular case. Both the clinical diagnosis and recognition of the underlying metabolic abnormality are important because they identify the specific abnormality that will be the base for treatment. There were 5 different cases in which a metabolic disorder leads to specific bone pathology, we discuss the pathogenesis of arterial calcifications and presents a mixed entity we call osteoporomalacia.
