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1.
Emerg Infect Dis ; 30(10): 2056-2069, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39320153

RESUMEN

In the United States in 2021, an outbreak of 4 cases of Burkholderia pseudomallei, the etiologic agent of melioidosis and a Tier One Select Agent (potential for deliberate misuse and subsequent harm), resulted in 2 deaths. The causative strain, B. pseudomallei ATS2021, was unintentionally imported into the United States in an aromatherapy spray manufactured in India. We established that ATS2021 represents a virulent strain of B. pseudomallei capable of robust formation of biofilm at physiologic temperatures that may contribute to virulence. By using mouse melioidosis models, we determined median lethal dose estimates and analyzed the bacteriologic and histopathologic characteristics of the organism, particularly the potential neurologic pathogenesis that is probably associated with the bimABm allele identified in B. pseudomallei strain ATS2021. Our data, combined with previous case reports and the identification of endemic B. pseudomallei strains in Mississippi, support the concept that melioidosis is emerging in the United States.


Asunto(s)
Burkholderia pseudomallei , Melioidosis , Burkholderia pseudomallei/genética , Burkholderia pseudomallei/patogenicidad , Melioidosis/microbiología , Melioidosis/epidemiología , Animales , Ratones , Virulencia , Estados Unidos/epidemiología , Humanos , Femenino , Modelos Animales de Enfermedad , Biopelículas , Enfermedades Transmisibles Importadas/microbiología , Enfermedades Transmisibles Importadas/epidemiología
2.
J Antimicrob Chemother ; 78(3): 810-816, 2023 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-36738250

RESUMEN

OBJECTIVES: To evaluate the in vitro activity and in vivo efficacy of delafloxacin against Bacillus anthracis, the causative agent of anthrax. METHODS: MICs were obtained according to CLSI guidelines for 30 virulent isolates and 14 attenuated antibiotic-resistant strains. For the in vivo efficacy study, mice were administered delafloxacin (30-62.5 mg/kg) subcutaneously, or ciprofloxacin (30 mg/kg) intraperitoneally beginning at either 24 or 48 ±â€Š1 h post-challenge (post-exposure prophylaxis) and continued every 12 h for 14 days with study termination on day 30. The mean inhaled dose in the study was approximately 103 × LD50 equivalents, and the range was 87-120 × LD50. RESULTS: Delafloxacin (MIC90 = 0.004 mg/L) was 16-fold more potent than ciprofloxacin (MIC90 = 0.06 mg/L) against a 30-strain set of virulent B. anthracis. Against a panel of attenuated antibiotic-resistant strains, delafloxacin demonstrated potency ≥128-fold over that observed with ciprofloxacin. When evaluated in vivo, mice treated with all delafloxacin doses tested at 24 h post-challenge demonstrated equivalent survival compared with mice treated with the positive control ciprofloxacin. Because of the high challenge dose of spores, mice treated at 48 h showed rapid and high mortality in all groups including the positive control. Surviving animals in all delafloxacin- and ciprofloxacin-treated groups (24 and 48 h) showed complete splenic clearance of infection and <2.2 × 103 cfu/g lung tissue. CONCLUSIONS: Given the high bar set by the 100 × LD50 challenge dose in this study, the results from delafloxacin treatment are promising for the treatment of inhaled anthrax.


Asunto(s)
Carbunco , Bacillus anthracis , Animales , Ratones , Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Ciprofloxacina , Pruebas de Sensibilidad Microbiana
3.
Bioorg Med Chem ; 25(10): 2743-2753, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28385597

RESUMEN

Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.


Asunto(s)
Acetatos/química , Barrera Hematoencefálica/metabolismo , Etanolamina/química , Fenoles/química , Administración Oral , Amidas/química , Animales , Área Bajo la Curva , Encéfalo/metabolismo , Ésteres/química , Semivida , Masculino , Ratones , Ratones Endogámicos C57BL , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacocinética , Curva ROC
4.
Bioorg Med Chem ; 24(22): 5842-5854, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27707627

RESUMEN

There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy. Ester prodrugs of sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One sobetirome prodrug, ethanolamine ester 11, was found to distribute more sobetirome to the brain compared to an equimolar peripheral dose of unmodified sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified sobetirome. Thus, these data indicate that an ester prodrug strategy applied to sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.


Asunto(s)
Acetatos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Ésteres/farmacología , Permeabilidad/efectos de los fármacos , Fenoles/farmacología , Profármacos/farmacología , Acetatos/síntesis química , Acetatos/química , Animales , Relación Dosis-Respuesta a Droga , Ésteres/síntesis química , Ésteres/química , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Fenoles/síntesis química , Fenoles/química , Profármacos/síntesis química , Profármacos/química , Relación Estructura-Actividad
5.
Angew Chem Int Ed Engl ; 54(33): 9696-9, 2015 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-26118368

RESUMEN

The endoplasmic reticulum (ER) plays critical roles in the processing of secreted and transmembrane proteins. To deliver small molecules to this organelle, we synthesized fluorinated hydrophobic analogues of the fluorophore rhodol. These cell-permeable fluorophores are exceptionally bright, with quantum yields of around 0.8, and they were found to specifically accumulate in the ER of living HeLa cells, as imaged by confocal laser scanning microscopy. To target a biological pathway controlled by the ER, we linked a fluorinated hydrophobic rhodol to 5-nitrofuran-2-acrylaldehyde. In contrast to an untargeted nitrofuran warhead, delivery of this electrophilic nitrofuran to the ER by the rhodol resulted in cytotoxicity comparable to the ER-targeted cytotoxin eeyarestatin I, and specifically inhibited protein processing by the ubiquitin-proteasome system. Fluorinated hydrophobic rhodols are outstanding fluorophores that enable the delivery of small molecules for targeting ER-associated proteins and pathways.


Asunto(s)
Portadores de Fármacos/química , Retículo Endoplásmico/metabolismo , Colorantes Fluorescentes/química , Nitrofuranos/administración & dosificación , Xantonas/química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/metabolismo , Sistemas de Liberación de Medicamentos , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/metabolismo , Halogenación , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Xantonas/síntesis química , Xantonas/metabolismo
6.
Microbiol Spectr ; 12(4): e0358623, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38391232

RESUMEN

Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.


Asunto(s)
Mpox , Orthopoxvirus , Viruela , Virus de la Viruela , Animales , Ratones , Humanos , Nucleósidos/uso terapéutico , Viruela/tratamiento farmacológico , Viruela/prevención & control , Modelos Animales de Enfermedad
7.
Antibiotics (Basel) ; 12(3)2023 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-36978372

RESUMEN

Burkholderia pseudomallei, the causative agent of the disease melioidosis, has been isolated from the environment in 45 countries. The treatment of melioidosis is complex, requiring lengthy antibiotic regimens, which can result in the relapse of the disease following treatment cessation. It is important that novel therapies to treat infections with B. pseudomallei be assessed in appropriate animal models, and discussions regarding the different protocols used between laboratories are critical. A 'deep dive' was held in October 2020 focusing on the use of the BALB/c mouse model and the inhalational route of infection to evaluate new antibiotic therapies.

8.
ACS Infect Dis ; 8(10): 2133-2148, 2022 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-36102590

RESUMEN

Polymers of d-glutamic acid (PDGA) form the capsule of the highly virulent Ames strain of B. anthracis. PDGA is antiphagocytic and weakly immunogenic; it enables the bacteria to evade the innate immune responses. CapD is an enzyme that catalyzes the covalent anchoring of PDGA. CapD is an Ntn-amido hydrolase that utilizes an internal Thr-352 as its nucleophile and general acid and base. An internal cleavage produces a free N-terminal Thr-352 and a short and long polypeptide chain. The chains were circularly permuted (CP) to move Thr-352 to the N-terminus of the polypeptide. We previously showed that a branched PEG-CapDS334C-CP could protect mice (80% survival) against a 5 LD50 challenge with B. anthracis Ames without the use of antibiotics, monoclonals, or vaccines. In attempts to improve the in vivo circulation time of CapD and enhance its avidity to its polymeric substrate, an Fc-domain of a mouse IgG1 was fused to CapDS334C-CP and the linker length and sequence were optimized. The resulting construct, Fc-CapDS334C-CP, then was pegylated with a linear 2 kDa mPEG at S334C to produce mPEG-Fc-CapDS334C-CP. Interestingly, the fusion of the Fc-domain and incorporation of the S334C mutation imparted acid stability, but slightly reduced the kcat (∼ 2-fold lower). In vivo, the measured protein concentration in sera was higher for the Fc-fusion constructs compared to the mPEG-Fc-CapDS334C-CP. However, the exposure calculated from measured sera enzymatic activity was higher for the mPEG-CapDS334C-CP. The pegylated Fc-fusion was less active than the PEG-CapDS334C-CP, but detectable in sera at 24 h by immunoblot. Here we describe the engineering of a soluble, active, pegylated Fc-fusion of B. anthracis CapD (mPEG-Fc-CapD-CP) with activity in vitro, in serum, and on encapsulated bacteria.


Asunto(s)
Carbunco , Bacillus anthracis , Animales , Carbunco/tratamiento farmacológico , Carbunco/microbiología , Antibacterianos/metabolismo , Bacillus anthracis/genética , Ácido Glutámico/metabolismo , Hidrolasas/metabolismo , Inmunoglobulina G/metabolismo , Ratones , Polietilenglicoles
9.
Lancet Infect Dis ; 20(9): e231-e237, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32563280

RESUMEN

The PALM trial in the Democratic Republic of the Congo identified a statistically significant survival benefit for two monoclonal antibody-based therapeutics in the treatment of acute Ebola virus disease; however, substantial gaps remain in improving the outcomes of acute Ebola virus disease and for the survivors. Ongoing efforts are needed to develop more effective strategies, particularly for individuals with severe disease, for prevention and treatment of viral persistence in immune-privileged sites, for optimisation of post-exposure prophylaxis, and to increase therapeutic breadth. As antibody-based approaches are identified and advanced, promising small-molecule antivirals currently in clinical stage development should continue to be evaluated for filovirus diseases, with consideration of their added value in combination approaches with bundled supportive care, their penetration in tissues of interest, the absence of interaction with glycoprotein-based vaccines, and filoviral breadth.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Vacunas contra el Virus del Ébola/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/terapia , Humanos , Profilaxis Posexposición
10.
ACS Med Chem Lett ; 10(1): 111-116, 2019 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-30655956

RESUMEN

Thyroid hormone (TH) action is of clinical interest in treating demyelinating diseases of the central nervous system (CNS). Two amide prodrugs of sobetirome, a potent thyroid hormone agonist, were previously shown to significantly improve CNS selective distribution of the parent drug through hydrolysis in the CNS by fatty acid amide hydrolase (FAAH). This concept is elaborated upon here with a series of 29 amide prodrugs targeting FAAH. We identify that conservative aliphatic modifications such as the N-methyl (4), N-ethyl (5), N-fluoroethyl (15), and N-cyclopropyl (18) substantially favor selective CNS distribution of the parent drug in mice. Additionally, lead compounds exhibit moderate to good rates of hydrolysis at FAAH in vitro suggesting both enzymatic and physicochemical properties are important parameters for optimization. Both 4 and 15 were orally bioavailable while retaining appreciable CNS parent drug delivery following an oral dose. The pharmacokinetic parameters of 4 over 24 h postdose (i.v. and p.o.) were determined.

11.
JCI Insight ; 4(8)2019 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-30996143

RESUMEN

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.


Asunto(s)
Acetatos/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Vaina de Mielina/efectos de los fármacos , Fenoles/farmacología , Hormonas Tiroideas/agonistas , Sustancia Blanca/efectos de los fármacos , Acetatos/uso terapéutico , Animales , Axones/efectos de los fármacos , Axones/patología , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Gliotoxina/toxicidad , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Transgénicos , Esclerosis Múltiple/etiología , Esclerosis Múltiple/patología , Vaina de Mielina/patología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/patología , Fenoles/uso terapéutico , Profármacos/farmacología , Profármacos/uso terapéutico , Remielinización/efectos de los fármacos , Remielinización/genética , Hormonas Tiroideas/administración & dosificación , Factores de Transcripción/genética , Sustancia Blanca/citología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología
12.
ACS Chem Neurosci ; 8(11): 2468-2476, 2017 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-28756656

RESUMEN

The blood-brain barrier (BBB) can be a substantial impediment to achieving therapeutic levels of drugs in the CNS. Certain chemical functionality such as the carboxylic acid is a general liability for BBB permeability preventing significant CNS distribution of a drug from a systemic dose. Here, we report a strategy for CNS-selective distribution of the carboxylic acid containing thyromimetic sobetirome using prodrugs targeted to fatty-acid amide hydrolase (FAAH), which is expressed in the brain. Two amide prodrugs of sobetirome were shown to be efficient substrates of FAAH with Vmax/KM values comparable to the natural endocannabinoid FAAH substrate anandamide. In mice, a systemic dose of sobetirome prodrug leads to a substantial ∼60-fold increase in brain distribution (Kp) of sobetirome compared to an equimolar systemic dose of the parent drug. The increased delivery of sobetirome to the brain from the prodrug was diminished by both pharmacological inhibition and genetic deletion of FAAH in vivo. The increased brain exposure of sobetirome arising from the prodrug corresponds to ∼30-fold increased potency in brain target engagement compared to the parent drug. These results suggest that FAAH-targeted prodrugs can considerably increase drug exposure to the CNS with a concomitant decrease in systemic drug levels generating a desirable distribution profile for CNS acting drugs.


Asunto(s)
Acetatos/farmacocinética , Amidohidrolasas/metabolismo , Fenoles/farmacocinética , Profármacos/farmacocinética , Activación Metabólica , Amidas/farmacocinética , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Animales , Ácidos Araquidónicos/metabolismo , Barrera Hematoencefálica , Química Encefálica , Endocannabinoides/metabolismo , Humanos , Hidrólisis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Ácidos Oléicos/metabolismo , Especificidad de Órganos , Alcamidas Poliinsaturadas/metabolismo , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato , Hormonas Tiroideas/fisiología , Distribución Tisular
13.
ACS Chem Biol ; 10(2): 570-6, 2015 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-25415586

RESUMEN

Inhibitors of the PI3-kinase/Akt (protein kinase B) pathway are under investigation as anticancer and antiviral agents. Akt inhibitor-IV (ChemBridge 5233705, CAS 681281-88-9, AKTIV), a small molecule reported to inhibit this pathway, exhibits potent anticancer and broad-spectrum antiviral activity. However, depending on concentration, this cationic benzimidazole derivative exhibits paradoxical positive or negative effects on the phosphorylation of Akt that are not well understood. To elucidate its mechanism of action, we investigated its spectroscopic properties. This compound proved to be sufficiently fluorescent (excitation λmax = 388 nm, emission λmax = 460 nm) to enable examination of its uptake and distribution in living mammalian cells. Despite a low quantum yield of 0.0016, imaging of HeLa cells treated with AKTIV (1 µM, 5 min) by confocal laser scanning microscopy, with excitation at 405 nm, revealed extensive accumulation in mitochondria. Treatment of Jurkat lymphocytes with 1 µM AKTIV for 15 min caused accumulation to over 250 µM in these organelles, whereas treatment with 5 µM AKTIV yielded concentrations of over 1 mM in mitochondria, as analyzed by flow cytometry. This massive loading resulted in swelling of these organelles, followed by their apparent disintegration. These effects were associated with profound disruption of cellular bioenergetics including mitochondrial depolarization, diminished mitochondrial respiration, and release of reactive oxygen species. Because mitochondria play key roles in both cancer proliferation and viral replication, we conclude that the anticancer and antiviral activities of AKTIV predominantly result from its direct and immediate effects on the structure and function of mitochondria.


Asunto(s)
Antineoplásicos/farmacología , Antivirales/farmacología , Bencimidazoles/farmacología , Benzotiazoles/farmacología , Mitocondrias/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antivirales/química , Antivirales/metabolismo , Bencimidazoles/química , Bencimidazoles/metabolismo , Benzotiazoles/química , Benzotiazoles/metabolismo , Citometría de Flujo , Células HeLa , Humanos , Células Jurkat , Potencial de la Membrana Mitocondrial , Microscopía Confocal , Estructura Molecular , Especies Reactivas de Oxígeno
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