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Introduction: Studies have shown that a diet high in fiber and prebiotics has a positive impact on human health due largely to the fermentation of these compounds by the gut microbiota. One underutilized source of fiber may be rice bran, a waste product of rice processing that is used most frequently as an additive to livestock feed but may be a good source of fibers and other phenolic compounds as a human diet supplement. Previous studies focused on specific compounds extracted from rice bran showed that soluble fibers extracted from rice bran can improve glucose response and reduce weight gain in mouse models. However, less is known about changes in the human gut microbiota in response to regular rice bran consumption. Methods: In this study, we used a Simulator of the Human Intestinal Microbial Ecology (SHIME®) to cultivate the human gut microbiota of 3 different donors in conditions containing either soluble or insoluble fiber fractions from rice bran. Using 16S rRNA amplicon sequencing and targeted metabolomics via Gas Chromatography-Mass Spectrometry, we explored how gut microbial communities developed provided different supplemental fiber sources. Results: We found that insoluble and soluble fiber fractions increased short-chain fatty acid production, indicating that both fractions were fermented. However, there were differences in response between donors, for example the gut microbiota from donor 1 increased acetic acid production with both fiber types compared with control; whereas for donors 2 and 3, butanoic acid production increased with ISF and SF supplementation. Both soluble and insoluble rice bran fractions increased the abundance of Bifidobacterium and Lachnospiraceae taxa. Discussion: Overall, analysis of the effect of soluble and insoluble rice bran fractions on the human in vitro gut microbiota and the metabolites produced revealed individually variant responses to these prebiotics.
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Ivermectin is a an anti-helminthic that is critical globally for both human and veterinary care. To the best of our knowledge, information available regarding the influence of ivermectin (IVM) on the gut microbiota has only been collected from diseased donors, who were treated with IVM alone or in combination with other medicines. Results thus obtained were influenced by multiple elements beyond IVM, such as disease, and other medical treatments. The research presented here investigated the impact of IVM on the gut microbial structure established in a Triple-SHIME® (simulator of the human intestinal microbial ecosystem), using fecal material from three healthy adults. The microbial communities were grown using three different culture media: standard SHIME media and SHIME media with either soluble or insoluble fiber added (control, SF, ISF). IVM introduced minor and temporary changes to the gut microbial community in terms of composition and metabolite production, as revealed by 16S rRNA amplicon sequencing analysis, flow cytometry, and GC-MS. Thus, it was concluded that IVM is not expected to induce dysbiosis or yield adverse effects if administered to healthy adults. In addition, the donor's starting community influences the relationship between IVM and the gut microbiome, and the soluble fiber component in feed could protect the gut microbiota from IVM; an increase in short-chain fatty acid production was predicted by PICRUSt2 and detected with IVM treatment.
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Microbioma Gastrointestinal , Ivermectina , Adulto , Humanos , Fezes , Microbioma Gastrointestinal/genética , Ivermectina/farmacologia , RNA Ribossômico 16S/genéticaRESUMO
Introduction: Following consumption of milk, lactose, a disaccharide of glucose and galactose, is hydrolyzed and absorbed in the upper gastrointestinal tract. However, hydrolysis and absorption are not always absolute, and some lactose will enter the colon where the gut microbiota is able to hydrolyze lactose and produce metabolic byproducts. Methods: Here, the impact of lactose on the gut microbiota of healthy adults was examined, using a short-term, in vitro strategy where fecal samples harvested from 18 donors were cultured anaerobically with and without lactose. The data were compiled to identify donor-independent responses to lactose treatment. Results and discussion: Metagenomic sequencing found that the addition of lactose decreased richness and evenness, while enhancing prevalence of the ß-galactosidase gene. Taxonomically, lactose treatment decreased relative abundance of Bacteroidaceae and increased lactic acid bacteria, Lactobacillaceae, Enterococcaceae, and Streptococcaceae, and the probiotic Bifidobacterium. This corresponded with an increased abundance of the lactate utilizers, Veillonellaceae. These structural changes coincided with increased total short-chain fatty acids (SCFAs), specifically acetate, and lactate. These results demonstrated that lactose could mediate the gut microbiota of healthy adults in a donor-independent manner, consistent with other described prebiotics, and provided insight into how dietary milk consumption may promote human health through modifications of the gut microbiome.
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Introduction: Fructooligosaccharides (FOS) are well-known carbohydrates that promote healthy gut microbiota and have been previously demonstrated to enhance levels of Bifidobacterium and Lactobacillus. Its bifidogenic properties are associated with positive health outcomes such as reduced obesity and anti-inflammatory properties, and, therefore, is in use as a prebiotic supplement to support healthy gut microbiota. However, the gut microbiota changes with age, which may lead to differential responses to treatments with prebiotics and other dietary supplements. Methods: To address this concern, we implemented a 24-h in vitro culturing method to determine whether FOS treatment in three different adult age groups would have a differential effect. The age groups of interest ranged from 25 to 70 years and were split into young adults, adults, and older adults for the purposes of this analysis. Metagenomics and short-chain fatty acid analysis were performed to determine changes in the structure and function of the microbial communities. Results: These analyses found that FOS created a bifidogenic response in all age groups, increased overall SCFA levels, decreased alpha diversity, and shifted the communities to be more similar in beta diversity metrics. However, the age groups differed in which taxa were most prevalent or most affected by FOS treatment. Discussion: Overall, the results of this study demonstrate the positive effects of FOS on the gut microbiome, and importantly, how age may play a role in the effectiveness of this prebiotic.
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As the demand for potable water increases, direct potable reuse of wastewater is an attractive alternative method to produce potable water. However, implementation of such a process will require the removal of emerging contaminants which could accumulate in the drinking water supply. Here, the removal of atrazine, a commonly used herbicide, has been investigated. Using real and synthetic wastewater, as well as sludge from two wastewater treatment facilities in the United States in Norman, Oklahoma and Fayetteville, Arkansas, atrazine removal has been investigated. Our results indicate that about 20% of the atrazine is removed by adsorption onto the particulate matter present. Significant biodegradation of atrazine was only observed under aerobic conditions for sludge from Norman, Oklahoma. Next-generation sequencing of the activated sludge revealed the abundance of Noncardiac with known atrazine degradation pathways in the Norman aerobic sludge, which is believed to be responsible for atrazine biodegradation in our study. The detection of these bacteria could also be used to determine the likelihood of biodegradation of atrazine for a given wastewater treatment facility.
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Atrazina , Poluentes Químicos da Água , Purificação da Água , Arkansas , Biodegradação Ambiental , Reatores Biológicos , Oklahoma , Esgotos , Eliminação de Resíduos Líquidos , Águas ResiduáriasRESUMO
The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug.IMPORTANCE Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.
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Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/uso terapêutico , Animais , Macaca , Infecções por Orthomyxoviridae/virologiaRESUMO
Direct potable reuse of wastewater is attractive as the demand for potable water increases. However, the presence of organic micropollutants in industrial and domestic wastewater is a major health and environmental concern. Conventional wastewater treatment processes are not designed to remove these compounds. Further many of these emerging pollutants are not regulated. Membrane bioreactor based biological wastewater treatment has recently become a preferred method for treating municipal and other industrial wastewaters. Here the removal of five selected micropollutants representing different classes of emerging micropollutants has been investigated using a membrane bioreactor. Acetaminophen, amoxicillin, atrazine, estrone, and triclosan were spiked into wastewaters obtained from a local wastewater treatment facility prior to introduction to the membrane bioreactor containing both anoxic and aerobic tanks. Removal of these compounds by adsorption and biological degradation was determined for both the anoxic and aerobic processes. The removal as a function of operating time was investigated. The results obtained here suggest that removal may be related to the chemical structure of the micropollutants.
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Reatores Biológicos , Membranas Artificiais , Águas Residuárias/química , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Poluentes Químicos da Água/análiseRESUMO
To develop agents for the treatment of infections caused by Mycobacterium tuberculosis, a novel phenotypic screen was undertaken that identified a series of 2-N-aryl thiazole-based inhibitors of intracellular Mycobacterium tuberculosis. Analogs were optimized to improve potency against an attenuated BSL2 H37Ra laboratory strain cultivated in human macrophage cells in vitro. The insertion of a carboxylic acid functionality resulted in compounds that retained potency and greatly improved microsomal stability. However, the strong potency trends we observed in the attenuated H37Ra strain were inconsistent with the potency observed for virulent strains in vitro and in vivo.
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Antibacterianos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Effluent samples from three water resource recovery facilities (WRRFs) were individually characterized for presence and concentration of 94 different chemicals of emerging concern (CECs), using analytical methods with reporting limits in the low-parts-per-trillion. Following CEC analysis, each sample was subjected to dead-end, pressurized membrane filtration with either a nanofiltration (NF) or reverse osmosis (RO) membrane. The majority of the measured CECs were rejected by both membranes by 1-log removal (90%) or greater. However, nine of the 94 CECs had average rejection rates by the NF membrane less than 90%. A multilevel, multivariable model was developed to predict the probable rejection coefficients of CECs with the studied NF membrane. The resulting Quantitative Molecular Properties Model (QMPM) predicted the NF rejection of CECs based on size, ionic charge, and hydrophobicity. The model parameters that successfully predicted NF rejection in bench testing were log (Kow/Kaw) and the polar surface area of the CEC molecule.
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Poluentes Químicos da Água/isolamento & purificação , Purificação da Água/métodos , Filtração , Membranas Artificiais , Recursos HídricosRESUMO
JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.
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In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
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As reuse of municipal water resource recovery facility (WRRF) effluent becomes vital to augment diminishing fresh drinking water resources, concern exists that conventional barriers may prove deficient, and the upcycling of chemicals of emerging concern (CECs) could prove harmful to human health and aquatic species if more effective and robust treatment barriers are not in place. A multiple month survey, of both primary and secondary effluents, from three (3) WRRFs, for 95 CECs was conducted in 2014 to classify CECs by their persistence through conventional water reclamation processes. By sampling the participating WRRF process trains at their peak performance (as determined by measured bulk organics and particulates removal), a short-list of recalcitrant CECs that warrant monitoring to assess treatment performance at advanced water reclamation and production facilities. The list of identified CECs for potable water reclamation (indirect or direct potable reuse) include a herbicide and its degradants, prescription pharmaceuticals and antibiotics, a female hormone, an artificial sweetener, and chlorinated flame retardants.
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Monitoramento Ambiental/métodos , Retardadores de Chama/análise , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Recursos Hídricos , Antibacterianos/análise , Cidades , Água Potável , Herbicidas/análise , Hormônios/análise , Humanos , Oklahoma , Preparações Farmacêuticas/análise , Esgotos , Edulcorantes/análise , TexasRESUMO
JNJ63623872 (formerly known as VX-787) is an inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit. This interaction blocks the cap-snatching activity of the virus that is essential for virus replication. Previously published work has documented antiviral activity of JNJ63623872 in cell culture and mouse infection studies. In this report, we extend the in vivo observations by comparing the efficacies of JNJ63623872 and oseltamivir in mice infected with influenza A/California/04/2009 (H1N1pdm) and A/Victoria/3/75 (H3N2) viruses. Animals received JNJ63623872 or oseltamivir orally twice daily for 10 days starting 2 h pre-infection. JNJ63623872 (2, 6, and 20 mg/kg/day) and oseltamivir (20 mg/kg/day) completely prevented death in the H1N1pdm virus infection. Weight loss at nadir was only 12% in mice receiving 2 mg/kg/day of JNJ63623872 compared to 23% and 32%, respectively, in oseltamivir-treated (20 mg/kg/day) and placebo groups. Lung hemorrhage scores, lung weights, and lung virus titers on day 6 were reduced in a dose-responsive manner by JNJ63623872 treatments, whereas oseltamivir treatments were not as effective. JNJ63623872 was less active against H3N2 virus infection, with more body weight loss occurring and only 30% survival at the 2-mg/kg/day dose. Lung scores, lung weights, and H3N2 viral titers in lungs of mice were reduced less by JNJ63623872 treatments compared to the H1N1pdm infection. Nevertheless, the 20-mg/kg/day dose of JNJ63623872 was more effective than oseltamivir (20 mg/kg/day) in improving body weight and reducing the severity of lung infection. JNJ63623872 appears to be an important new drug candidate to treat influenza A H1N1pdm and H3N2 virus infections.
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Antivirais/uso terapêutico , Indóis/uso terapêutico , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/uso terapêutico , Animais , Descoberta de Drogas , Quimioterapia Combinada , Indóis/administração & dosagem , Pulmão/virologia , Camundongos , Infecções por Orthomyxoviridae/virologia , Oseltamivir/administração & dosagem , Piridinas , Pirimidinas , Pirróis , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
PURPOSE: To describe a life-threatening complication during endovascular aneurysm repair that was caused by a series of errors. CASE REPORT: A 64-year-old man received a Zenith aortouni-iliac stent-graft for a 61-mm saccular aortic aneurysm. During retrieval of the delivery system, the sheath became dislodged from the common femoral artery. Reintroduction caused the top cap to disengage from the pusher rod because the pin vice had not been tightened as per the instructions for use. Subsequent traction was applied but the delivery system could not be withdrawn from the sheath, thus it was decided to remove the delivery system and sheath en masse. On removal, the distal sealing stent was found deformed and wedged between the top cap and the sheath. Perforation of the common iliac artery by the avulsed stent was treated with iliac limb extension before contralateral iliac plug and femorofemoral bypass graft were performed as planned. The patient made an uneventful recovery. CONCLUSION: Trapping of the distal sealing stent between the top cap and the pusher rod of the Zenith graft is possible and can be prevented by securing the pin vice prior to retrieval. Description of this complication may prevent similar occurrences in future.
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Aneurisma Aórtico/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Procedimentos Endovasculares/instrumentação , Artéria Ilíaca/cirurgia , Falha de Prótese , Stents , Lesões do Sistema Vascular/etiologia , Aneurisma Aórtico/diagnóstico por imagem , Aortografia/métodos , Implante de Prótese Vascular/efeitos adversos , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/efeitos adversos , Humanos , Doença Iatrogênica , Artéria Ilíaca/diagnóstico por imagem , Artéria Ilíaca/lesões , Masculino , Erros Médicos , Pessoa de Meia-Idade , Desenho de Prótese , Fatores de Risco , Resultado do Tratamento , Lesões do Sistema Vascular/diagnóstico por imagem , Lesões do Sistema Vascular/terapiaRESUMO
Symptomatic common carotid artery (CCA) occlusion is an uncommon occurrence that may require surgical intervention. We aim to describe a case of CCA occlusion that presented with the unusual symptom of recurrent syncope. A 69-year-old lady presented with a history of recurrent syncopal episodes and amaurosis fugax associated with left leg weakness. She was found to have a right CCA occlusion on duplex ultrasound and angiography. She underwent a right common carotid endarterectomy and intraoperative findings revealed a heavily calcified plaque in the CCA just proximal to the bifurcation with organised thrombus filling the CCA proximally. CCA occlusion can rarely present with recurrent syncopal episodes. Surgery may be curative.
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Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.
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Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent in vitro and in vivo properties have been identified. To evaluate the in vivo efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.
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Antivirais/farmacologia , Compostos Aza/farmacologia , Indóis/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Projetos de Pesquisa , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Compostos Aza/síntese química , Compostos Aza/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Expressão Gênica , Indóis/síntese química , Indóis/farmacocinética , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Testes de Função Respiratória , Análise de Sobrevida , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
BACKGROUND: The 2005 outbreak of Marburg virus (MARV) infection in Angola was the most lethal MARV infection outbreak in history, with a case-fatality rate (90%) similar to that for Zaire ebolavirus (EBOV) infection. However, very little is known about the pathogenicity of MARV Angola, as few studies have been conducted to date. Therefore, the immune response was examined in MARV Angola-infected nonhuman primates. METHODS: Cynomolgus macaques were infected with MARV Angola and monitored for survival. The effect of MARV Angola on the immune system was examined by immunophenotyping whole-blood and by analyzing cytokine and chemokine levels in plasma and spleen specimens, using flow cytometry. RESULTS: The prominent clinical findings were rapid onset of disease and death (mean time after infection, 6.7 days), fever, depression, anorexia, petechial rash, and lymphopenia. Specifically, T, B, and natural killer cells were severely depleted in the blood by day 6. The typical cytokine storm was present, with levels of interferon γ, tumor necrosis factor, interleukin 6, and CCL2 rising in the blood early during infection. CONCLUSIONS: MARV Angola displayed the same virulence and disease pathology as EBOV. MARV Angola appears to cause a more rapid onset and severe outcome of infection than other MARV strains.
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Doença do Vírus de Marburg/imunologia , Marburgvirus/imunologia , Primatas/imunologia , Angola , Animais , Quimiocina CCL2/imunologia , Modelos Animais de Doenças , Ebolavirus/imunologia , Feminino , Interferon gama/imunologia , Interleucina-6/imunologia , Linfócitos/imunologia , Linfócitos/virologia , Macaca/imunologia , Macaca/virologia , Doença do Vírus de Marburg/virologia , Primatas/virologia , Baço/imunologia , Baço/virologia , Fator de Necrose Tumoral alfa/imunologia , Virulência/imunologiaRESUMO
New drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drug-resistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 µg/ml and 0.08 to 5.48 µg/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 µg/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 µg/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc-486 in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.