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1. Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Author

Martin J. McPhillie, Ying Zhou, Mark R. Hickman, James A. Gordon, Christopher R. Weber, Qigui Li, Patty J. Lee, Kangsa Amporndanai, Rachel M. Johnson, Heather Darby, Stuart Woods, Zhu-hong Li, Richard S. Priestley, Kurt D. Ristroph, Scott B. Biering, Kamal El Bissati, Seungmin Hwang, Farida Esaa Hakim, Sarah M. Dovgin, Joseph D. Lykins, Lucy Roberts, Kerrie Hargrave, Hua Cong, Anthony P. Sinai, Stephen P. Muench, Jitender P. Dubey, Robert K. Prud'homme, Hernan A. Lorenzi, Giancarlo A. Biagini, Silvia N. Moreno, Craig W. Roberts, Svetlana V. Antonyuk, Colin W. G. Fishwick, and Rima McLeod

Subjects
Toxoplasma gondii, Plasmodium falciparum, cytochrome bc1, tetrahydroquinolone, nanoformulation, structure-guided design, Microbiology, QR1-502
Abstract

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

Published
2020
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2. Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations

Author

Kamal El Bissati, Henry Redel, Li-Min Ting, Joseph D. Lykins, Martin J. McPhillie, Rajendra Upadhya, Patrick M. Woster, Nigel Yarlett, Kami Kim, and Louis M. Weiss

Subjects
polyamine, Plasmodium, malaria, spermidine, spermine, spermidine synthase, Microbiology, QR1-502
Abstract

Twenty-two compounds belonging to several classes of polyamine analogs have been examined for their ability to inhibit the growth of the human malaria parasite Plasmodium falciparum in vitro and in vivo. Four lead compounds from the thiourea sub-series and one compound from the urea-based analogs were found to be potent inhibitors of both chloroquine-resistant (Dd2) and chloroquine-sensitive (3D7) strains of Plasmodium with IC50 values ranging from 150 to 460 nM. In addition, the compound RHW, N1,N7-bis (3-(cyclohexylmethylamino) propyl) heptane-1,7-diamine tetrabromide was found to inhibit Dd2 with an IC50 of 200 nM. When RHW was administered to P. yoelii-infected mice at 35 mg/kg for 4 days, it significantly reduced parasitemia. RHW was also assayed in combination with the ornithine decarboxylase inhibitor difluoromethylornithine, and the two drugs were found not to have synergistic antimalarial activity. Furthermore, these inhibitors led to decreased cellular spermidine and spermine levels in P. falciparum, suggesting that they exert their antimalarial activities by inhibition of spermidine synthase.

Published
2019
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3. CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii

Author

Joseph D. Lykins, Ekaterina V. Filippova, Andrei S. Halavaty, George Minasov, Ying Zhou, Ievgeniia Dubrovska, Kristin J. Flores, Ludmilla A. Shuvalova, Jiapeng Ruan, Kamal El Bissati, Sarah Dovgin, Craig W. Roberts, Stuart Woods, Jon D. Moulton, Hong Moulton, Martin J. McPhillie, Stephen P. Muench, Colin W. G. Fishwick, Elisabetta Sabini, Dhanasekaran Shanmugam, David S. Roos, Rima McLeod, Wayne F. Anderson, and Huân M. Ngô

Subjects
Toxoplasma gondii, PPMO, phosphoglycerate mutase, nucleoside diphoshate kinase, ribulose-3-phosphate epimerase, ribose-5-phosphate isomerase, Microbiology, QR1-502
Abstract

Toxoplasma gondii, an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized. Crystallography revealed insights into the overall structure, protein oligomeric states and molecular details of active sites important for ligand recognition. Literature and molecular modeling suggested potential inhibitors and druggability. The targets were further studied with vivoPMO to interrupt enzyme synthesis, identifying the targets as potentially important to parasitic replication and, therefore, of therapeutic interest. Targeted vivoPMO resulted in statistically significant perturbation of parasite replication without concomitant host cell toxicity, consistent with a previous CRISPR/Cas9 screen showing PGM, RPE, and RPI contribute to parasite fitness. PGM, RPE, and RPI have the greatest promise for affecting replication in tachyzoites. These targets are shared between other medically important parasites and may have wider therapeutic potential.

Published
2018
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4. The Effect of Delays in Second-Dose Antibiotics on Patients with Severe Sepsis and Septic Shock

Author

Erron M. Rourke, Natasha N Pettit, Eric P. Keast, Michelle D. Hughes, Jason A. Kopec, Joseph D. Lykins, Michael A. Ward, Hani I. Kuttab, and Brooke Ward

Subjects
Adult, Male, medicine.medical_specialty, medicine.drug_class, Antibiotics, Article, Drug Administration Schedule, Time-to-Treatment, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Humans, Dosing, Hospital Mortality, Severe sepsis, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Septic shock, 030208 emergency & critical care medicine, General Medicine, Middle Aged, medicine.disease, Shock, Septic, Anti-Bacterial Agents, Intravenous antibiotics, Shock (circulatory), Emergency Medicine, Administration, Intravenous, Female, medicine.symptom, business, Emergency Service, Hospital
Abstract

Background Early antibiotics are fundamental to sepsis management. Second-dose antibiotic delays were associated with increased mortality in a recent study. Study objectives include: 1) determine factors associated with delays in second-dose antibiotic administration; 2) evaluate if delays influence clinical outcomes. Methods ED-treated adults (≥18 years; n = 1075) with severe sepsis or septic shock receiving ≥2 doses of intravenous antibiotics were assessed, retrospectively, for second-dose antibiotic delays (dose time > 25% of recommended interval). Predictors of delay and impact on outcomes were determined, controlling for MEDS score, 30 mL/kg fluids and antibiotics within three hours of sepsis onset, lactate, and renal failure, among others. Results In total, 335 (31.2%) patients had delayed second-dose antibiotics. A total of 1864 second-dose antibiotics were included, with 354 (19.0%) delays identified by interval (delayed/total doses): 6-h (36/67) = 53.7%; 8-h (165/544) = 30.3%; 12-h (114/436) = 26.1%; 24-h (21/190) = 8.2%; 48-h (0/16) = 0%. In-hospital mortality in the timely group was 15.5% (shock-17.6%) and 13.7% in the delayed group (shock-16.9%). Increased odds of delay were observed for ED boarding (OR 2.54, 95% 1.81–3.55), shorter dosing intervals (6/8-h- OR 2.99, 95% CI 1.95–4.57; 12-h- OR 2.46, 95% CI 1.72–3.51), receiving 30 mL/kg fluids by three hours (OR 1.42, 95% CI 1.06–1.90), and renal failure (OR 2.57, 95% CI 1.50–4.39). Delays were not associated with increased mortality (OR 0.87, 95% CI 0.58–1.29) or other outcomes. Conclusions Factors associated with delayed second-dose antibiotics include ED boarding, antibiotics requiring more frequent dosing, receiving 30 mL/kg fluid, and renal failure. Delays in second-dose administration were not associated with mortality or other outcomes.

Published
2021

6. Evaluation and Predictors of Fluid Resuscitation in Patients with Severe Sepsis and Septic Shock

Author

Stephen Hall, Kristen Wroblewski, Michelle D. Hughes, Hani I. Kuttab, Omobolawa Y. Kukoyi, Michael A. Ward, Eric P. Keast, Jason A. Kopec, and Joseph D. Lykins

Subjects
Male, medicine.medical_specialty, Resuscitation, Comorbidity, Critical Care and Intensive Care Medicine, Article, Odds, Sepsis, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Patient Admission, Sex Factors, Internal medicine, medicine, Humans, Hospital Mortality, Retrospective Studies, Septic shock, business.industry, Age Factors, 030208 emergency & critical care medicine, Retrospective cohort study, Odds ratio, Middle Aged, medicine.disease, Shock, Septic, Intensive Care Units, 030228 respiratory system, Heart failure, Fluid Therapy, Kidney Failure, Chronic, Female, business, Emergency Service, Hospital, Cohort study
Abstract

Objectives Rapid fluid resuscitation has become standard in sepsis care, despite "low-quality" evidence and absence of guidelines for populations "at risk" for volume overload. Our objectives include as follows: 1) identify predictors of reaching a 30 mL/kg crystalloid bolus within 3 hours of sepsis onset (30by3); 2) assess the impact of 30by3 and fluid dosing on clinical outcomes; 3) examine differences in perceived "at-risk" volume-sensitive populations, including end-stage renal disease, heart failure, obesity, advanced age, or with documentation of volume "overload" by bedside examination. Design Retrospective cohort study. All outcome analyses controlled for sex, end-stage renal disease, heart failure, sepsis severity (severe sepsis vs septic shock), obesity, Mortality in Emergency Department Sepsis score, and time to antibiotics. Setting Urban, tertiary care center between January 1, 2014, and May 31, 2017. Patients Emergency Department treated adults (age ≥18 yr; n = 1,032) with severe sepsis or septic shock. Interventions Administration of IV fluids by bolus. Measurements and main results In total, 509 patients received 30by3 (49.3%). Overall mortality was 17.1% (n = 176), with 20.4% mortality in the shock group. Patients who were elderly (odds ratio, 0.62; 95% CI, 0.46-0.83), male (odds ratio, 0.66; CI, 0.49-0.87), obese (odds ratio, 0.18; CI, 0.13-0.25), or with end-stage renal disease (odds ratio, 0.23; CI, 0.13-0.40), heart failure (odds ratio, 0.42; CI, 0.29-0.60), or documented volume "overload" (odds ratio, 0.30; CI, 0.20-0.45) were less likely to achieve 30by3. Failure to meet 30by3 had increased odds of mortality (odds ratio, 1.52; CI, 1.03-2.24), delayed hypotension (odds ratio, 1.42; CI, 1.02-1.99), and increased ICU stay (~2 d) (β = 2.0; CI, 0.5-3.6), without differential effects for "at-risk" groups. Higher fluid volumes administered by 3 hours correlated with decreased mortality, with a plateau effect between 35 and 45 mL/kg (p Conclusions Failure to reach 30by3 was associated with increased odds of in-hospital mortality, irrespective of comorbidities. Predictors of inadequate resuscitation can be identified, potentially leading to interventions to improve survival. These findings are retrospective and require future validation.

Published
2019

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