26 results on '"J. Stone Doggett"'
Search Results
2. Acridones Are Highly Potent Inhibitors of Toxoplasma gondii Tachyzoites
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Jane Xu Kelly, Rozalia A. Dodean, Papireddy Kancharla, Erin V. McConnell, Jan M. Boitz Zarella, J. Stone Doggett, and P. Holland Alday
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0301 basic medicine ,biology ,Chemistry ,Cytochrome bc1 ,Drug discovery ,030106 microbiology ,Toxoplasma gondii ,biology.organism_classification ,medicine.disease ,In vitro ,Toxoplasmosis ,Acridone ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Infectious Diseases ,Biochemistry ,In vivo ,parasitic diseases ,Dihydroorotate dehydrogenase ,medicine - Abstract
Acridone derivatives, which have been shown to have in vitro and in vivo activity against Plasmodium spp, inhibit Toxoplasma gondii proliferation at picomolar concentrations. Using enzymatic assays, we show that acridones inhibit both T. gondii cytochrome bc1 and dihydroorotate dehydrogenase and identify acridones that bind preferentially to the Qi site of cytochrome bc1. We identify acridones that have efficacy in a murine model of systemic toxoplasmosis. Acridones have potent activity against T. gondii and represent a promising new class of preclinical compounds.
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- 2021
3. Effective Therapy Targeting Cytochrome bc 1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection
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Pallavi Singh, Michael K. Riscoe, Aaron Nilsen, Choukri Ben Mamoun, Anasuya Chattopadhyay Pal, Isaline Renard, Shalev Gihaz, Pratap Vydyam, Rolf W. Winter, Madelyn Kumar, Sovitj Pou, Rozalia Dodean, Joy E. Chiu, Jose Thekkiniath, J. Stone Doggett, and Lisa Frueh
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Pharmacology ,Babesiosis ,Parasitemia ,Biology ,medicine.disease ,biology.organism_classification ,Virology ,Infectious Diseases ,Parasitology ,parasitic diseases ,Babesia ,medicine ,Pharmacology (medical) ,Mode of action ,Pathogen ,Atovaquone ,Malaria ,medicine.drug - Abstract
An effective strategy to control blood-borne diseases and prevent outbreak recrudescence involves targeting conserved metabolic processes that are essential for pathogen viability. One such target for Plasmodium and Babesia, the infectious agents of malaria and babesiosis, respectively, is the mitochondrial cytochrome bc1 protein complex, which can be inhibited by endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen Babesia duncani to evaluate the structure-activity relationship, safety, efficacy and mode of action of ELQs. We identified a potent and highly selective ELQ prodrug (ELQ-502), which, alone, or in combination with atovaquone, eliminates B. microti and B. duncani infections in vitro and in mouse models of parasitemia and lethal infection. The strong efficacy at low dose, excellent safety, bioavailability and long half-life of this experimental therapy makes it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.
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- 2021
4. Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis
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Kayode K. Ojo, Molly C. McCloskey, Igor Bruzual, Suzanne Scheele, Amy E. DeRocher, Samuel L.M. Arnold, J. Stone Doggett, Grant R. Whitman, Erkang Fan, Marilyn Parsons, Wenlin Huang, Kasey Rivas, Erin V. McConnell, Rama Subba Rao Vidadala, Ryan Choi, Matthew A. Hulverson, Wesley C. Van Voorhis, Lynn K. Barrett, and Dustin J. Maly
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0301 basic medicine ,medicine.drug_class ,Protozoan Proteins ,Administration, Oral ,Carboxamide ,In Vitro Techniques ,Pharmacology ,Pyrazolopyrimidine ,Mice ,Major Articles and Brief Reports ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Immunology and Allergy ,030212 general & internal medicine ,Protein kinase A ,Protein Kinase Inhibitors ,biology ,Kinase ,Toxoplasma gondii ,medicine.disease ,biology.organism_classification ,Toxoplasmosis ,Pyrimidines ,Toxoplasmosis, Animal ,030104 developmental biology ,Infectious Diseases ,chemistry ,Area Under Curve ,Toxoplasmosis, Cerebral ,Pyrazoles ,Female - Abstract
Bumped kinase inhibitors (BKIs) have been shown to be potent inhibitors of Toxoplasma gondii calcium-dependent protein kinase 1. Pyrazolopyrimidine and 5-aminopyrazole-4-carboxamide scaffold-based BKIs are effective in acute and chronic experimental models of toxoplasmosis. Through further exploration of these 2 scaffolds and a new pyrrolopyrimidine scaffold, additional compounds have been identified that are extremely effective against acute experimental toxoplasmosis. The in vivo efficacy of these BKIs demonstrates that the cyclopropyloxynaphthyl, cyclopropyloxyquinoline, and 2-ethoxyquinolin-6-yl substituents are associated with efficacy across scaffolds. In addition, a broad range of plasma concentrations after oral dosing resulted from small structural changes to the BKIs. These select BKIs include anti-Toxoplasma compounds that are effective against acute experimental toxoplasmosis and are not toxic in human cell assays, nor to mice when administered for therapy. The BKIs described here are promising late leads for improving anti-Toxoplasma therapy.
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- 2018
5. Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection
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Joy E. Chiu, J. Stone Doggett, Pratap Vydyam, Rozalia Dodean, Pallavi Singh, Sovitj Pou, Anasuya Chattopadhyay Pal, Jose Thekkiniath, Rolf W. Winter, Shalev Gihaz, Isaline Renard, Aaron Nilsen, Choukri Ben Mamoun, Madelyn Kumar, and Michael K. Riscoe
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biology ,Babesiosis ,Parasitemia ,Prodrug ,biology.organism_classification ,medicine.disease ,Virology ,parasitic diseases ,Babesia ,medicine ,Mode of action ,Pathogen ,Atovaquone ,Malaria ,medicine.drug - Abstract
Targeting conserved metabolic processes that are essential for viability of pathogens, such as Plasmodium and Babesia that cause blood-borne diseases, is an effective strategy to eliminate malaria and babesiosis infections with no recrudescence. One interesting target is the mitochondrial cytochrome bc1 complex, which could be inhibited by drugs such as endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen Babesia duncani to evaluate the structure-activity relationship, safety, efficacy and mode of action of ELQs. We identified a potent and highly selective ELQ prodrug (ELQ-502), which alone or in combination with atovaquone eliminates B. microti and B. duncani infections in vitro and in mouse models of parasitemia and lethal infection. The strong efficacy at low dose, excellent safety, bioavailability and long half-life of this experimental therapy makes it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.
- Published
- 2021
6. Malignant (Necrotizing) Otitis Externa
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Brian Wong and J. Stone Doggett
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medicine.medical_specialty ,medicine.drug_class ,business.industry ,Antibiotics ,Histology ,Disease ,Malignant otitis externa ,Facial nerve ,Dermatology ,medicine.anatomical_structure ,Otitis ,otorhinolaryngologic diseases ,medicine ,Ear canal ,Necrotizing otitis externa ,medicine.symptom ,business - Abstract
Malignant or necrotizing otitis externa is a rare, invasive infection that begins in the external ear canal and spreads to adjacent tissue. Severe infection may extend to the base of the skull or intra-cranially. Medical knowledge of malignant otitis externa is primarily derived from retrospective case series. The majority of reported patients are elderly diabetics infected with Pseudomonas aeruginosa. Patients typically present with otalgia and otorrhea with little evidence of systemic illness. Diagnosis is based on clinical presentation, radiographic imaging with CT or MRI, and tissue histology and culture. Treatment requires prolonged systemic antibiotics and surgery is not required for cure in most cases. Mortality for malignant otitis externa has improved since the disease was first characterized, but a significant number of patients have recurrent disease and require multiple courses of antibiotics. Clinicians should suspect malignant otitis externa in diabetic patients who present with symptoms of otitis externa.
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- 2021
7. Acute Suppurative Thyroiditis
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Brian Wong and J. Stone Doggett
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endocrine system ,medicine.medical_specialty ,Percutaneous ,endocrine system diseases ,medicine.diagnostic_test ,business.industry ,Fistula ,Airway obstruction ,medicine.disease ,Dysphagia ,Surgery ,Pyriform Sinus ,Fine-needle aspiration ,medicine ,medicine.symptom ,Abscess ,business ,Subacute thyroiditis - Abstract
Acute suppurative thyroiditis is a medical emergency that usually presents with anterior neck pain, fever, and dysphagia and can lead to airway obstruction. Thyroid infection is rare, and an underlying immune deficiency or thyroid abnormality is present in most cases. The majority of immunocompetent patients will have a pyriform sinus fistula. Differentiating acute suppurative thyroiditis from painful subacute thyroiditis or invasive head and neck infections usually requires diagnostic imaging with CT or ultrasound. In certain instances, tissue histology obtained by fine needle aspiration may be required to definitively diagnose acute suppurative thyroiditis. Obtaining cultures by aspiration, surgery, or percutaneous drainage is required to guide antibiotic therapy. The majority of acute suppurative thyroiditis cases are caused by Staphylococcus aureus and Streptococcus species. Acute suppurative thyroiditis should be treated urgently with antibiotics and abscess drainage.
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- 2021
8. The Need for Antiviral Drugs for Pandemic Coronaviruses From a Global Health Perspective
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Angela Holly Villamagna, Sara J. Gore, James S. Lewis, and J. Stone Doggett
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medicine.medical_specialty ,viruses ,coronavirus ,global health ,viral pneumonia ,Disease ,medicine.disease_cause ,drug discovery ,antiviral drugs ,Pharmacotherapy ,Pandemic ,Global health ,Medicine ,Intensive care medicine ,Coronavirus ,lcsh:R5-920 ,business.industry ,COVID-19 ,General Medicine ,medicine.disease ,target product profile ,Clinical trial ,Viral pneumonia ,Perspective ,lcsh:Medicine (General) ,business ,Viral load ,outbreak preparedness - Abstract
Respiratory failure due to SARS-CoV-2 has caused widespread mortality, creating an urgent need for effective treatments and a long-term need for antivirals for future emergent coronaviruses. Pharmacotherapy for respiratory viruses has largely been unsuccessful with the exception of early treatment of influenza viruses, which shortens symptom duration and prevents infection in close contacts. Under the rapidly evolving circumstances of the COVID-19 pandemic, most clinical trials of experimental treatments in the United States have focused on later stages of the disease process. Worldwide, the clinical studies of the most impactful drugs, remdesivir and dexamethasone in ACTT-1, RECOVERY, and Solidarity, have studied hospitalized patients. Less than half of clinical trials in the U.S. have investigated oral agents, and the majority have taken place in hospitals at a disease stage where the viral load is already decreasing. The limited success of treatments for respiratory viruses and the viral dynamics of COVID-19 suggest that an antiviral therapy with the greatest impact against pandemic coronaviruses would be orally administered, well-tolerated, target a highly conserved viral protein or host-coronavirus interaction and could be used effectively throughout the world, including resource-poor settings. We examine the treatment of respiratory viral infections and current clinical trials for COVID-19 to provide a framework for effective antiviral therapy and prevention of future emergent coronaviruses and call attention to the need for continued preclinical drug discovery.
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- 2020
9. One health therapeutics: Target-Based drug development for cryptosporidiosis and other apicomplexa diseases
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Dennis Imhof, Kayode K. Ojo, Pablo Winzer, Joachim Müller, Samuel L.M. Arnold, Lynn K. Barrett, Thomas J. Kennedy, J. Stone Doggett, Nicoleta Anghel, Deborah A. Schaefer, Sangun Lee, Saul Tzipori, Wesley C. Van Voorhis, Roberto Sánchez-Sánchez, Grant R. Whitman, Luis Miguel Ortega-Mora, Ignacio Ferre, Wenlin Huang, Andrew Hemphill, Dustin J. Maly, Rama Subba Rao Vidadala, Michael W. Riggs, Erkang Fan, Matthew A. Hulverson, Ryan Choi, and Dana P. Betzer
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0301 basic medicine ,animal diseases ,030231 tropical medicine ,Cryptosporidiosis ,Article ,Apicomplexa ,03 medical and health sciences ,0302 clinical medicine ,Piperidines ,parasitic diseases ,medicine ,Animals ,Humans ,One Health ,General Veterinary ,biology ,630 Agriculture ,Antiparasitic Agents ,business.industry ,Toxoplasma gondii ,General Medicine ,030108 mycology & parasitology ,medicine.disease ,biology.organism_classification ,Virology ,Toxoplasmosis ,Neospora caninum ,Cryptosporidium parvum ,Pyrimidines ,Drug development ,Quinolines ,Parasitology ,Livestock ,business - Abstract
This is a review of the development of bumped-kinase inhibitors (BKIs) for the therapy of One Health parasitic apicomplexan diseases. Many apicomplexan infections are shared between humans and livestock, such as cryptosporidiosis and toxoplasmosis, as well as livestock only diseases such as neosporosis. We have demonstrated proof-of-concept for BKI therapy in livestock models of cryptosporidiosis (newborn calves infected with Cryptosporidium parvum), toxoplasmosis (pregnant sheep infected with Toxoplasma gondii), and neosporosis (pregnant sheep infected with Neospora caninum). We discuss the potential uses of BKIs for the treatment of diseases caused by apicomplexan parasites in animals and humans, and the improvements that need to be made to further develop BKIs.
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- 2020
10. Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts
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Rolf W. Winter, Tracey L. Schultz, Vern B. Carruthers, Aaron Nilsen, Sovitj Pou, Alyssa J. Miller, Michael K. Riscoe, Rozalia Dodean, Lev N. Zakharov, Igor Bruzual, and J. Stone Doggett
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medicine.drug_class ,Cmax ,Carbonates ,Pharmacology ,Quinolones ,Carbonate ester ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Medicine ,Animals ,Pharmacology (medical) ,Experimental Therapeutics ,Prodrugs ,Adverse effect ,030304 developmental biology ,0303 health sciences ,biology ,030306 microbiology ,business.industry ,Area under the curve ,Toxoplasma gondii ,Brain ,Esters ,Prodrug ,Quinolone ,biology.organism_classification ,medicine.disease ,Toxoplasmosis ,3. Good health ,Bioavailability ,Infectious Diseases ,Toxoplasmosis, Animal ,chemistry ,business ,Toxoplasma - Abstract
Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for the T. gondii cytochrome b over the human cytochrome b. Despite oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a six-fold increase in both Cmax (maximum plasma concentration) and AUC (area under the curve) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in greater efficacy than the equivalent dose of ELQ-316 against acute toxoplasmosis and had similar efficacy against latent toxoplasmosis compared to intraperitoneal administration of ELQ-316. Carbonate ester prodrugs are a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.
- Published
- 2020
11. Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains
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J. Stone Doggett, William J. Sullivan, and Jennifer Martynowicz
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0303 health sciences ,biology ,Combination therapy ,030306 microbiology ,business.industry ,Clindamycin ,Toxoplasma gondii ,Pharmacology ,medicine.disease ,biology.organism_classification ,Toxoplasmosis ,3. Good health ,03 medical and health sciences ,Pyrimethamine ,In vivo ,Medicine ,Cyst ,Guanabenz ,business ,030304 developmental biology ,medicine.drug - Abstract
Toxoplasma gondii, an obligate intracellular parasite that can cause life-threatening acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute infection, is currently refractory to clinically available therapeutics. Recently, we and others have discovered drugs capable of significantly reducing brain cyst burden in latently infected mice, but not to undetectable levels. In this study, we examined the use of novel combination therapies possessing multiple mechanisms of action in mouse models of latent toxoplasmosis. Our drug regimens included combinations of pyrimethamine, clindamycin, guanabenz, and endochin-like quinolones (ELQs), and were administered to two different mouse strains in an attempt to eradicate brain tissue cysts. We observed mouse strain-dependent effects with these drug treatments: pyrimethamine + guanabenz showed synergistic efficacy in C57BL/6 mice, yet did not improve upon guanabenz monotherapy in BALB/c mice. Contrary to promising in vitro results demonstrating toxicity to bradyzoites, we observed an antagonistic effect between guanabenz + ELQ-334 in vivo. While we were unable to completely eliminate brain cyst burden, we found that a combination treatment of ELQ-334 + pyrimethamine impressively reduced brain cysts to 95% in C57BL/6 mice, which approaches the limit of detection. These analyses highlight the importance of evaluating anti-infective drugs in multiple mouse strains and will help inform further preclinical cocktail therapy studies designed to treat chronic toxoplasmosis.
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- 2020
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12. Efficacy of Guanabenz Combination Therapy against Chronic Toxoplasmosis across Multiple Mouse Strains
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William J. Sullivan, Jennifer Martynowicz, and J. Stone Doggett
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Combination therapy ,03 medical and health sciences ,Mice ,In vivo ,medicine ,Animals ,Pharmacology (medical) ,Cyst ,Experimental Therapeutics ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Mice, Inbred BALB C ,Guanabenz ,biology ,030306 microbiology ,business.industry ,Clindamycin ,Toxoplasma gondii ,biology.organism_classification ,medicine.disease ,Toxoplasmosis ,3. Good health ,Mice, Inbred C57BL ,Infectious Diseases ,Pyrimethamine ,Toxoplasmosis, Animal ,Immunology ,business ,Toxoplasma ,medicine.drug - Abstract
Toxoplasma gondii, an obligate intracellular parasite that can cause life-threatening acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute infection, is currently refractory to clinically available therapeutics. Recently, we and others have discovered drugs capable of significantly reducing the brain cyst burden in latently infected mice, but not to undetectable levels. In this study, we examined the use of novel combination therapies possessing multiple mechanisms of action in mouse models of latent toxoplasmosis. Our drug regimens included combinations of pyrimethamine, clindamycin, guanabenz, and endochin-like quinolones (ELQs) and were administered to two different mouse strains in an attempt to eradicate brain tissue cysts. We observed mouse strain-dependent effects with these drug treatments: pyrimethamine-guanabenz showed synergistic efficacy in C57BL/6 mice yet did not improve upon guanabenz monotherapy in BALB/c mice. Contrary to promising in vitro results demonstrating toxicity to bradyzoites, we observed an antagonistic effect between guanabenz and ELQ-334 in vivo. While we were unable to completely eliminate the brain cyst burden, we found that a combination treatment with ELQ-334 and pyrimethamine impressively reduced the brain cyst burden by 95% in C57BL/6 mice, which approached the limit of detection. These analyses highlight the importance of evaluating anti-infective drugs in multiple mouse strains and will help inform further preclinical studies of cocktail therapies designed to treat chronic toxoplasmosis.
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- 2020
13. Targeted Structure–Activity Analysis of Endochin-like Quinolones Reveals Potent Qi and Qo Site Inhibitors of Toxoplasma gondii and Plasmodium falciparum Cytochrome bc1 and Identifies ELQ-400 as a Remarkably Effective Compound against Acute Experimental Toxoplasmosis
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J. Stone Doggett, Sovitj Pou, Michael K. Riscoe, Igor Bruzual, Alina Krollenbrock, Aaron Nilsen, Rolf W. Winter, Erin V. McConnell, Martin J. Smilkstein, Rozalia Dodean, and Lev N. Zakharov
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0301 basic medicine ,Ubiquinol ,biology ,Cytochrome bc1 ,Cytochrome b ,Chemistry ,medicine.drug_class ,030106 microbiology ,Toxoplasma gondii ,Plasmodium falciparum ,Drug resistance ,biology.organism_classification ,Quinolone ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Infectious Diseases ,parasitic diseases ,medicine ,Atovaquone ,medicine.drug - Abstract
Cytochrome bc1 inhibitors have been broadly studied as human and veterinary medicines and agricultural fungicides. For the most part, cytochrome bc1 inhibitors compete with ubiquinol at the ubiquinol oxidation (Qo) site or with ubiquinone at the quinone reduction (Qi) site. 4(1 H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1 H)-Quinolones that inhibit the Qi site are highly effective against toxoplasmosis, malaria, and babesiosis and do not inhibit human cytochrome bc1. We tested a series of 4(1 H)-Quinolones against wild-type and drug resistant strains of Toxoplasma gondii and Plasmodium falciparum. These experiments identified very potent compounds that inhibit T. gondii proliferation at picomolar concentrations. The most potent compounds target the Qo site, and for these compounds, an alkyl side chain confers potency against T. gondii greater than that of bulkier side chains. Our experiments also show that substituents on the quinolone ring influenced selectivity between T. gondii and P. falciparum and between Qo and Qi site-mediated activity. Comparison of the parasite cytochrome b sequences identified amino acids that are associated with drug resistance in P. falciparum that exist naturally in wild-type T. gondii. These underlying differences may influence drug susceptibility. Finally, a Qo site active 4(1 H)-quinolone-3-diarylether tested in a murine model of toxoplasmosis was superior to atovaquone, resulting in survival from Type I strain T. gondii infection. These experiments identify highly effective compounds for toxoplasmosis and provide valuable insight into the structure-activity relationship of cytochrome bc1 inhibitors.
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- 2018
14. Extended-spectrum antiprotozoal bumped kinase inhibitors: A review
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Andrew Hemphill, Dustin J. Maly, Ethan A. Merritt, Marilyn Parsons, Audrey O.T. Lau, Daniel K. Howe, Ryan Choi, Samuel L.M. Arnold, Erkang Fan, Michael W. Riggs, Robert H. Mealey, Kayode K. Ojo, Matthew A. Hulverson, J. Stone Doggett, and Wesley C. Van Voorhis
- Subjects
0301 basic medicine ,Pyridines ,medicine.drug_class ,Immunology ,Antiprotozoal Agents ,MAP2K2 ,Biology ,Article ,Apicomplexa ,03 medical and health sciences ,medicine ,Animals ,Humans ,Protein phosphorylation ,Protein kinase A ,Protein Kinase Inhibitors ,Protozoan Infections ,Kinase ,Imidazoles ,General Medicine ,Protein-Tyrosine Kinases ,biology.organism_classification ,3. Good health ,Cell biology ,030104 developmental biology ,Infectious Diseases ,Biochemistry ,Antiprotozoal ,Benzimidazoles ,Parasitology ,Parasite protein ,Function (biology) - Abstract
Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites’ survival and proliferation. In this review, we review efficacy against the kinase target, the parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped-kinase inhibitors.
- Published
- 2017
15. Endochin-Like Quinolones Exhibit Promising Efficacy Against Neospora Caninum in vitro and in Experimentally Infected Pregnant Mice
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Adriana Aguado-Martínez, Sovitj Pou, Andrew Hemphill, Michael K. Riscoe, Nicoleta Anghel, Pablo Winzer, Aaron Nilsen, Vreni Balmer, Mona Roozbehani, J. Stone Doggett, and Joachim Müller
- Subjects
0301 basic medicine ,mouse model ,030106 microbiology ,Andrology ,cytochromeb ,03 medical and health sciences ,Neospora ,medicine ,Parasite hosting ,mitochondrion ,IC50 ,endochin-like quinolones ,Original Research ,Pregnancy ,lcsh:Veterinary medicine ,General Veterinary ,biology ,electron microscopy ,630 Agriculture ,Babesiosis ,biology.organism_classification ,medicine.disease ,Neospora caninum ,In vitro ,Toxoplasmosis ,3. Good health ,lcsh:SF600-1100 ,570 Life sciences ,Veterinary Science ,vertical transmission ,Toxoplasma - Abstract
We report on the efficacy of selected endochin-like quinolones (ELQs) against N. caninum tachyzoites grown in human foreskin fibroblasts (HFF), and in a pregnant BALB/c mouse model. Fourteen ELQs were screened against transgenic N. caninum tachyzoites expressing β-galactosidase (Nc-βgal). Drugs were added concomitantly to infection and the values for 50% proliferation inhibition (IC50) were determined after 3 days. Three compounds exhibited IC50 values below 0.1 nM, 3 ELQs had IC50s between 0.1 and 1 nM, for 7 compounds values between 1 and 10 nM were noted, and one compound had an IC50 of 22.4 nM. Two compounds, namely ELQ-316 and its prodrug ELQ-334 with IC50s of 0.66 and 3.33 nM, respectively, were previously shown to display promising activities against experimental toxoplasmosis and babesiosis caused by Babesia microti in mice, and were thus further studied. They were assessed in long-term treatment assays by exposure of infected HFF to ELQs at 0.5 μM concentration, starting 3 h after infection and lasting for up to 17 days followed by release of drug pressure. Results showed that the compounds substantially delayed parasite proliferation, but did not exert parasiticidal activities. TEM of drug treated parasites detected distinct alterations within the parasite mitochondria, but not in other parasite organelles. Assessment of safety of ELQ-334 in the pregnant mouse model showed that the compound did not interfere in fertility or pregnancy outcome. In N. caninum infected pregnant mice treated with ELQ-334 at 10 mg/kg/day for 5 days, neonatal mortality (within 2 days post partum) was found in 7 of 44 pups (15.9%), but no postnatal mortality was noted, and vertical transmission was reduced by 49% compared to the placebo group, which exhibited 100% vertical transmission, neonatal mortality in 15 of 34 pups (44%), and postnatal mortality for 18 of the residual 19 pups during the 4 weeks follow-up. These findings encourage more research on the use of ELQs for therapeutic options against N. caninum infection.
- Published
- 2018
16. Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone
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Alexander J. Allen, J. Stone Doggett, Isaac P. Forquer, Douglas A. Preston, Lauren Lawres, Azan Z. Virji, Jialing Mao, Aaron Nilsen, Choukri Ben Mamoun, Isaline Renard, Linda K. Bockenstedt, Igor Bruzual, Rolf W. Winter, David J. Hinrichs, Alexia A. Belperron, Pierre Boulard, Vidya Prasanna Kumar, Sovitj Pou, Aprajita Garg, Keith W. Wegmann, Michael K. Riscoe, and Eduardo X. Rodriguez
- Subjects
0301 basic medicine ,Combination therapy ,030106 microbiology ,Immunology ,Mice, SCID ,Pharmacology ,Biology ,Quinolones ,Azithromycin ,Babesia microti ,Article ,03 medical and health sciences ,Mice ,Babesiosis ,medicine ,Immunology and Allergy ,Potency ,Animals ,Prodrugs ,Research Articles ,Atovaquone ,Quinine ,Immunologic Deficiency Syndromes ,Clindamycin ,Prodrug ,medicine.disease ,Virology ,3. Good health ,030104 developmental biology ,medicine.drug - Abstract
Human babesiosis is a tick-borne multisystem disease, and current treatments have both adverse side effects and a significant rate of drug failure. Lawres et al. report that endochin-like quinolones, in combination with atovaquone, cure experimental babesiosis in immunodeficient mice., Human babesiosis is a tick-borne multisystem disease caused by Babesia species of the apicomplexan phylum. Most clinical cases and fatalities of babesiosis are caused by Babesia microti. Current treatment for human babesiosis consists of two drug combinations, atovaquone + azithromycin or quinine + clindamycin. These treatments are associated with adverse side effects and a significant rate of drug failure. Here, we provide evidence for radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone (ELQ) prodrug and atovaquone. In vivo efficacy studies in mice using ELQ-271, ELQ-316, and the ELQ-316 prodrug, ELQ-334, demonstrated excellent growth inhibitory activity against the parasite, with potency equal to that of orally administered atovaquone at 10 mg/kg. Analysis of recrudescent parasites after ELQ or atovaquone monotherapy identified genetic substitutions in the Qi or Qo sites, respectively, of the cytochrome bc1 complex. Impressively, a combination of ELQ-334 and atovaquone, at doses as low as 5.0 mg/kg each, resulted in complete clearance of the parasite with no recrudescence up to 122 d after discontinuation of therapy. These results will set the stage for future clinical evaluation of ELQ and atovaquone combination therapy for treatment of human babesiosis.
- Published
- 2016
17. BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection
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Jose Thekkiniath, J. Stone Doggett, Lauren Lawres, Benjamin A. Perrin, Sara Mootien, Michel Ledizet, Scott C. Williams, Choukri Ben Mamoun, Peter J. Krause, and Meital Gewirtz
- Subjects
Male ,0301 basic medicine ,Microbiology (medical) ,Erythrocytes ,Blood transfusion ,animal diseases ,medicine.medical_treatment ,Antigens, Protozoan ,Enzyme-Linked Immunosorbent Assay ,Babesia microti ,Serology ,Mice ,03 medical and health sciences ,Immune system ,Antigen ,Babesiosis ,parasitic diseases ,medicine ,Animals ,Humans ,Serologic Tests ,Cells, Cultured ,biology ,business.industry ,biology.organism_classification ,medicine.disease ,Virology ,030104 developmental biology ,Infectious disease (medical specialty) ,Babesia ,biology.protein ,Female ,Parasitology ,Antibody ,business - Abstract
Human babesiosis is an emerging zoonotic infectious disease caused by intraerythrocytic protozoan parasites of the genus Babesia. Most cases of human babesiosis are caused by Babesia microti and often manifest in individuals over the age of 50 years or in patients with a compromised immune system. Patients who develop symptomatic B. microti infections usually experience months of asymptomatic infection after the acute infection has resolved. About one-fifth of B. microti-infected adults never develop symptoms. These asymptomatically infected individuals sometimes donate blood and thus can transmit B. microti through blood transfusion. Current assays for detection of active B. microti infections can be used to screen donor blood prior to transfusion, but they rely primarily on microscopy or PCR methods, which have sensitivity and technical limitations. Here we report the development of an antigen capture enzyme-linked immunosorbent assay (BmGPAC) based on a major secreted immunodominant antigen of B. microti (BmGPI12/BmSA1), and we provide evidence that this assay is superior for detection of active B. microti infections, compared to available microscopy methods and serological assays. The assay has been evaluated using supernatants of B. microti-infected erythrocytes cultured in vitro, sera from B. microti-infected laboratory mice, and sera from wild mice and human patients. Our data suggest that the BmGPAC assay is a reliable assay for detection of active B. microti infections and is superior to real-time PCR and antibody assays for diagnosis of acute B. microti infections, screening of the blood supply, and epidemiological surveys of humans and animal reservoir hosts.
- Published
- 2018
18. Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance
- Author
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Jeremie Vendome, Yan Ling, Roland A. Cooper, Pradeep K. Singh, Liselle F. Guiang, Elena Fernández Álvaro, Kazuyoshi Aso, Laura A. Kirkman, Björn F.C. Kafsack, Carl Nathan, Lei Shi, Rong Wang, Joseph Visone, Purnima Bhanot, Patrick K Tumwebaze, Masanori Kawasaki, Ryoma Hara, Kavitha Govindasamy, Alexis Dziedziech, George Sukenick, Hao Fan, Mayako Michino, Rei Okamoto, J. Stone Doggett, Philip J. Rosenthal, Xinran Tong, Igor Bruzual, Kenjiro Sato, Michael Foley, Toshihiro Imaeda, Laura M. Sanz, Daniel Mota, Wenhu Zhan, and Gang Lin
- Subjects
0301 basic medicine ,Plasmodium ,Proteasome Endopeptidase Complex ,Plasmodium falciparum ,Mutant ,malaria ,Protozoan Proteins ,proteasome inhibitors ,Drug resistance ,Pharmacology ,Microbiology ,collateral sensitivity ,Bortezomib ,Antimalarials ,Lactones ,03 medical and health sciences ,chemistry.chemical_compound ,parasitic diseases ,medicine ,Humans ,Artemisinin ,Multidisciplinary ,biology ,Chemistry ,Drug Resistance, Microbial ,Biological Sciences ,biology.organism_classification ,Carfilzomib ,Artemisinins ,3. Good health ,030104 developmental biology ,PNAS Plus ,artemisinin ,Proteasome ,Proteasome inhibitor ,Oligopeptides ,medicine.drug - Abstract
Significance Protozoal proteasome is a validated target for antimalarial drug development, but species selectivity of reported inhibitors is suboptimal. Here we identify inhibitors with improved selectivity for malaria proteasome β5 subunit over each active subunit of human proteasomes. These compounds kill the parasite in each stage of its life cycle. They interact synergistically with a β2 inhibitor and with artemisinin. Resistance to the β5 inhibitor arose through a point mutation in the nonproteolytic β6 subunit. The same mutation made the mutant strain more sensitive to a β2 inhibitor and less fit to withstand irradiation. These findings reveal complex interplay among proteasome subunits and introduce the prospect that combined inhibition of β2 and β5 subunits can afford synergy and thwart resistance., We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.
- Published
- 2018
19. SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1
- Author
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Amy E. DeRocher, Kasey Rivas, Nina Isoherranen, Suzanne Scheele, Dale J. Kempf, J. Stone Doggett, Eugenio L. de Hostos, Keshia M. Kerchner, Marilyn Parsons, Dustin J. Maly, Matthew A. Hulverson, Gail M. Freiberg, Lynn K. Barrett, Wesley C. Van Voorhis, Ryan Choi, Rama Subba Rao Vidadala, Georg Neckermann, Wim G. J. Hol, Zhongsheng Zhang, Kayode K. Ojo, Latha Kallur Siddaramaiah, Igor Bruzual, Wenlin Huang, Erkang Fan, Matthew D Kurnick, and Ethan A. Merritt
- Subjects
biology ,medicine.drug_class ,Peritoneal fluid ,Organic Chemistry ,Toxoplasma gondii ,Carboxamide ,Spleen ,Pharmacology ,biology.organism_classification ,Biochemistry ,3. Good health ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Plasma exposure ,Oral administration ,Enzyme inhibitor ,Drug Discovery ,biology.protein ,medicine ,Growth inhibition - Abstract
We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from T. gondii. The current work, through structure–activity relationship studies, led to the discovery of compounds (34 and 35) with improved characteristics over the starting inhibitor 1 in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds 34 and 35 were further demonstrated to be more effective than 1 in a mouse infection model and markedly reduced the amount of T. gondii in the brain, spleen, and peritoneal fluid, and 35 given at 20 mg/kg eliminated T. gondii from the peritoneal fluid.
- Published
- 2015
20. Genetic Evidence for Cytochrome b Qi Site Inhibition by 4(1H)-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii
- Author
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P. Holland Alday, J. Stone Doggett, Aaron Nilsen, Igor Bruzual, Choukri Ben Mamoun, Michael K. Riscoe, Rolf W. Winter, and Sovitj Pou
- Subjects
0301 basic medicine ,medicine.drug_class ,Antimycin A ,Biology ,Quinolones ,03 medical and health sciences ,chemistry.chemical_compound ,parasitic diseases ,medicine ,Pharmacology (medical) ,Experimental Therapeutics ,Pharmacology ,Cytochrome bc1 ,Cytochrome b ,Toxoplasma gondii ,Cytochromes b ,medicine.disease ,biology.organism_classification ,Quinolone ,Virology ,Toxoplasmosis ,Mitochondria ,030104 developmental biology ,Infectious Diseases ,chemistry ,Mechanism of action ,Coenzyme Q – cytochrome c reductase ,medicine.symptom ,Toxoplasma - Abstract
Toxoplasma gondii is an apicomplexan parasite that causes fatal and debilitating brain and eye disease. Endochinlike quinolones (ELQs) are preclinical compounds that are efficacious against apicomplexan-caused diseases, including toxoplasmosis, malaria, and babesiosis. Of the ELQs, ELQ-316 has demonstrated the greatest efficacy against acute and chronic experimental toxoplasmosis. Although genetic analyses in other organisms have highlighted the importance of the cytochrome bc 1 complex Q i site for ELQ sensitivity, the mechanism of action of ELQs against T. gondii and the specific mechanism of ELQ-316 remain unknown. Here, we describe the selection and genetic characterization of T. gondii clones resistant to ELQ-316. A T. gondii strain selected under ELQ-316 drug pressure was found to possess a Thr222-Pro amino acid substitution that confers 49-fold resistance to ELQ-316 and 19-fold resistance to antimycin, a well-characterized Q i site inhibitor. These findings provide further evidence for ELQ Q i site inhibition in T. gondii and greater insight into the interactions of Q i site inhibitors with the apicomplexan cytochrome bc 1 complex.
- Published
- 2016
21. Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis
- Author
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Nina Isoherranen, Tracey L. Schultz, Amy E. DeRocher, Kayode K. Ojo, Jennifer A. Zambriski, Erkang Fan, Dale J. Kempf, Marilyn Parsons, Dustin J. Maly, Wesley C. Van Voorhis, Gail M. Freiberg, Wim G. J. Hol, Latha Kallur Siddaramaiah, Ethan A. Merritt, Rama Subba Rao Vidadala, Ryan Choi, Kasey Rivas, Matthew A. Hulverson, J. Stone Doggett, Suzanne Scheele, Kennan C. Marsh, Lynn K. Barrett, Wenlin Huang, Vern B. Carruthers, Igor Bruzual, and Zhongsheng Zhang
- Subjects
0301 basic medicine ,Central Nervous System ,030106 microbiology ,hERG ,Antiprotozoal Agents ,Administration, Oral ,Spleen ,Pharmacology ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Dogs ,Parasitic Sensitivity Tests ,In vivo ,Drug Discovery ,parasitic diseases ,medicine ,Animals ,Protein kinase A ,Protein Kinase Inhibitors ,Cardiotoxicity ,Mice, Inbred BALB C ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Toxoplasma gondii ,Haplorhini ,biology.organism_classification ,medicine.disease ,Toxoplasmosis ,In vitro ,Ether-A-Go-Go Potassium Channels ,Rats ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Drug Design ,biology.protein ,Molecular Medicine ,Female ,Protein Kinases ,Toxoplasma - Abstract
New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses anti-toxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human Ether-à-go-go-Related Gene (hERG) inhibitory activity, associated with long Q-T syndrome, and, consequently, presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new anti-toxoplasmosis therapy.
- Published
- 2016
22. Cystic Neutrophilic Granulomatous Mastitis: Association With Gram-Positive Bacilli and Corynebacterium
- Author
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Morgan Ballard, Arpana Naik, Megan L. Troxell, Rodney F. Pommier, John T. Vetto, Nicole T. Gordon, and J. Stone Doggett
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,medicine.drug_class ,Antibiotics ,Corynebacterium ,Granulomatous mastitis ,law.invention ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,law ,Biopsy ,medicine ,Humans ,Cyst ,030212 general & internal medicine ,Granulomatous Mastitis ,Gram-Positive Bacterial Infections ,Aged ,biology ,medicine.diagnostic_test ,Corynebacterium Infections ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,biology.organism_classification ,Mastitis ,Gram staining ,Infectious disease (medical specialty) ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Objectives: To determine whether cystic neutrophilic granulomatous mastitis (CNGM) can be associated with Gram-positive bacilli and Corynebacterium Methods: We reviewed our experience with 35 granulomatous mastitis patients over a 10-year period, including histologic pattern, Gram stain and other microbiologic data, clinical presentation, treatment and outcome. Results: Biopsies from 19 patients demonstrated CNGM, while 16 patients had other patterns of granulomatous mastitis. Gram-positive organisms were seen within microcystic spaces in 16/19 CNGM, but 0/16 non-CNGM patients ( P = .000). Culture or molecular studies demonstrated Corynebacterium species in three, all CNGM. Patients with CNGM were more likely to be younger, of Hispanic ethnicity, and born outside of the United States. Granulomatous mastitis resolved after a protracted course with widely variable treatment (antibiotics, surgery, steroids). Conclusions: Our data further support CNGM as an infectious disease; further study of Corynebacterium -directed therapy in CNGM is needed.
- Published
- 2016
23. Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers
- Author
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J. Stone Doggett, Yuexin Li, Eileen Ryan, Kasiram Katneni, Michael W. Mather, April M. Pershing, Sovitj Pou, Aaron Nilsen, David J. Hinrichs, Karen L. White, Ian Bathurst, Susan A. Charman, Allison M. Stickles, Rolf W. Winter, Isaac P. Forquer, Jane X. Kelly, Galen P. Miley, Akhil B. Vaidya, Jeremy N. Burrows, Michael K. Riscoe, and Lev N. Zakharov
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,medicine.drug_class ,Plasmodium falciparum ,Pharmacology ,Quinolones ,010402 general chemistry ,01 natural sciences ,Article ,Antimalarials ,Inhibitory Concentration 50 ,Chloroquine ,Drug Discovery ,medicine ,Animals ,Humans ,biology ,010405 organic chemistry ,Chemistry ,Drug discovery ,Rational design ,biology.organism_classification ,medicine.disease ,Quinolone ,3. Good health ,0104 chemical sciences ,Rats ,Multiple drug resistance ,HEK293 Cells ,Molecular Medicine ,Atovaquone ,Malaria ,medicine.drug - Abstract
The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
- Published
- 2014
24. Necrotizing Soft Tissue Infections
- Author
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J. Stone Doggett and Brian Wong
- Subjects
medicine.medical_specialty ,medicine.drug_class ,business.industry ,Antibiotics ,Surgical debridement ,Soft tissue ,medicine.disease ,Surgery ,Broad spectrum ,Antibiotic therapy ,Cellulitis ,medicine ,Soft tissue infection ,business ,Skin Findings - Abstract
Diabetics are more susceptible to skin and soft tissue infections, and in current studies, up to half of patients who develop necrotizing soft tissue infection have diabetes. Patients typically present with acute, severe illness and prominent skin findings. However, a percentage of patients with necrotizing soft tissue infection will be difficult to delineate from cellulitis. Laboratory and radiographic scoring systems have been proposed to aid in the diagnosis of necrotizing soft tissue infections, but surgical evaluation remains the definitive means of diagnosis. Aggressive emergent surgical debridement is essential to reduce morbidity and mortality and should be coupled with broad empiric antibiotic therapy. When diabetics present with soft tissue infection, physicians should consider the possibility of underlying necrotizing infection and pursue surgical evaluation if there are signs of systemic illness, characteristic skin findings, failure to respond to antibiotics, or characteristic radiographic findings.
- Published
- 2013
25. Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria
- Author
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Keith W. Wegmann, Aaron Nilsen, Jane X. Kelly, Erin W. Riscoe, J. Stone Doggett, David J. Hinrichs, Sovitj Pou, Yuexin Li, Rolf W. Winter, and Michael K. Riscoe
- Subjects
Drug ,media_common.quotation_subject ,Plasmodium falciparum ,Drug Resistance ,Drug resistance ,Biology ,Pharmacology ,chemistry.chemical_compound ,Antimalarials ,Inhibitory Concentration 50 ,Mice ,In vivo ,Chloroquine ,medicine ,Animals ,Pharmacology (medical) ,Experimental Therapeutics ,media_common ,Molecular Structure ,Aryl ,Plasmodium yoelii ,medicine.disease ,biology.organism_classification ,Malaria ,Infectious Diseases ,chemistry ,medicine.drug - Abstract
Sontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains of Plasmodium falciparum in vitro . We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC 50 s) against drug-sensitive and multidrug-resistant strains and in vivo efficacy against patent infections of Plasmodium yoelii in mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.
- Published
- 2012
26. Lyme Disease in Oregon ▿
- Author
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Robert Gresbrink, Curt A. Gleaves, Paul Metz, Sue J. Kohlhepp, David N. Gilbert, and J. Stone Doggett
- Subjects
Microbiology (medical) ,Lyme Disease ,biology ,Ixodes ,Incidence (epidemiology) ,Incidence ,fungi ,Bacteriology ,medicine.disease ,biology.organism_classification ,bacterial infections and mycoses ,Virology ,Oregon ,Lyme disease ,Ixodes pacificus ,Borrelia burgdorferi ,medicine ,Prevalence ,Lyme disease microbiology ,Animals ,Humans ,Arachnid Vectors ,Exposure history ,geographic locations ,health care economics and organizations - Abstract
The incidence of Lyme disease in Oregon is calculated from cases reported to the Oregon State Health Division. We reviewed the exposure history of reported cases of Lyme disease and performed field surveys for infected Ixodes pacificus ticks. The incidence of Lyme disease correlated with the distribution of infected I . pacificus ticks.
- Published
- 2008
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