Publications by authors named "Christina A Bulman"

17 Publications

  • Page 1 of 1

Comparative Performance of Latest-Generation and FDA-Cleared Serology Tests for the Diagnosis of Chagas Disease.

J Clin Microbiol 2021 05 19;59(6). Epub 2021 May 19.

Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA

Confirmed diagnosis of chronic Chagas disease (CD) requires positive results by two different IgG serology tests. Variable sensitivity has been reported among tests and in different geographic regions. Inadequate specificity presents a particular challenge in low-prevalence settings such as the United States. This study provides a direct comparison of the latest-generation IgG serology assays with four previously assessed FDA-cleared tests. Seven hundred ten blood donor plasma specimens were evaluated by Wiener Lisado and Wiener v.4.0 enzyme-linked immunosorbent assays (ELISAs) and Abbott PRISM Chagas chemiluminescent assay (ChLIA). Sensitivity and specificity were assessed relative to infection status as determined by the original blood donation testing algorithm. All three latest-generation assays demonstrated 100% specificity (95% confidence interval [CI], 98.6 to 100.0). Wiener Lisado, Wiener v.4.0, and Abbott PRISM had sensitivities of 97.1% (95% CI, 95.1 to 98.4), 98.9% (95% CI, 97.4 to 99.6), and 95.5% (95% CI, 93.2 to 97.3), respectively. As with previously evaluated FDA-cleared tests, all three assays had the highest reactivity and sensitivity in samples from donors born in South America and lowest reactivity and sensitivity in specimens from those born in Mexico, with intermediate results in specimens from Central American donors. Wiener v.4.0 had the highest diagnostic sensitivity in all comparisons. Our findings suggest that the latest-generation CD serology tests could improve diagnostic sensitivity without affecting specificity.
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http://dx.doi.org/10.1128/JCM.00158-21DOI Listing
May 2021

The Eagle effect in the Wolbachia-worm symbiosis.

Parasit Vectors 2021 Feb 24;14(1):118. Epub 2021 Feb 24.

Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.

Background: Onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) are two human neglected tropical diseases that cause major disabilities. Mass administration of drugs targeting the microfilarial stage has reduced transmission and eliminated these diseases in several countries but a macrofilaricidal drug that kills or sterilizes the adult worms is critically needed to eradicate the diseases. The causative agents of onchocerciasis and lymphatic filariasis are filarial worms that harbor the endosymbiotic bacterium Wolbachia. Because filarial worms depend on Wolbachia for reproduction and survival, drugs targeting Wolbachia hold great promise as a means to eliminate these diseases.

Methods: To better understand the relationship between Wolbachia and its worm host, adult Brugia pahangi were exposed to varying concentrations of doxycycline, minocycline, tetracycline and rifampicin in vitro and assessed for Wolbachia numbers and worm motility. Worm motility was monitored using the Worminator system, and Wolbachia titers were assessed by qPCR of the single copy gene wsp from Wolbachia and gst from Brugia to calculate ICs and in time course experiments. Confocal microscopy was also used to quantify Wolbachia located at the distal tip region of worm ovaries to assess the effects of antibiotic treatment in this region of the worm where Wolbachia are transmitted vertically to the microfilarial stage.

Results: Worms treated with higher concentrations of antibiotics had higher Wolbachia titers, i.e. as antibiotic concentrations increased there was a corresponding increase in Wolbachia titers. As the concentration of antibiotic increased, worms stopped moving and never recovered despite maintaining Wolbachia titers comparable to controls. Thus, worms were rendered moribund by the higher concentrations of antibiotics but Wolbachia persisted suggesting that these antibiotics may act directly on the worms at high concentration. Surprisingly, in contrast to these results, antibiotics given at low concentrations reduced Wolbachia titers.

Conclusion: Wolbachia in B. pahangi display a counterintuitive dose response known as the "Eagle effect." This effect in Wolbachia suggests a common underlying mechanism that allows diverse bacterial and fungal species to persist despite exposure to high concentrations of antimicrobial compounds. To our knowledge this is the first report of this phenomenon occurring in an intracellular endosymbiont, Wolbachia, in its filarial host.
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http://dx.doi.org/10.1186/s13071-020-04545-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905570PMC
February 2021

Drugs that target early stages of Onchocerca volvulus: A revisited means to facilitate the elimination goals for onchocerciasis.

PLoS Negl Trop Dis 2021 02 18;15(2):e0009064. Epub 2021 Feb 18.

Molecular Parasitology, Lindsey F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.

Several issues have been identified with the current programs for the elimination of onchocerciasis that target only transmission by using mass drug administration (MDA) of the drug ivermectin. Alternative and/or complementary treatment regimens as part of a more comprehensive strategy to eliminate onchocerciasis are needed. We posit that the addition of "prophylactic" drugs or therapeutic drugs that can be utilized in a prophylactic strategy to the toolbox of present microfilaricidal drugs and/or future macrofilaricidal treatment regimens will not only improve the chances of meeting the elimination goals but may hasten the time to elimination and also will support achieving a sustained elimination of onchocerciasis. These "prophylactic" drugs will target the infective third- (L3) and fourth-stage (L4) larvae of Onchocerca volvulus and consequently prevent the establishment of new infections not only in uninfected individuals but also in already infected individuals and thus reduce the overall adult worm burden and transmission. Importantly, an effective prophylactic treatment regimen can utilize drugs that are already part of the onchocerciasis elimination program (ivermectin), those being considered for MDA (moxidectin), and/or the potential macrofilaricidal drugs (oxfendazole and emodepside) currently under clinical development. Prophylaxis of onchocerciasis is not a new concept. We present new data showing that these drugs can inhibit L3 molting and/or inhibit motility of L4 at IC50 and IC90 that are covered by the concentration of these drugs in plasma based on the corresponding pharmacological profiles obtained in human clinical trials when these drugs were tested using various doses for the therapeutic treatments of various helminth infections.
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http://dx.doi.org/10.1371/journal.pntd.0009064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891776PMC
February 2021

An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease.

Pathogens 2021 Jan 14;10(1). Epub 2021 Jan 14.

Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, 4523 Clayton Ave., St. Louis, MO 63110, USA.

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against spp. (adult and pre-adult ) confirmed activity for 13 drugs (the majority having IC < 10 μM), and a counter screen of a subset against microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs.
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http://dx.doi.org/10.3390/pathogens10010071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830784PMC
January 2021

Repurposing Auranofin and Evaluation of a New Gold(I) Compound for the Search of Treatment of Human and Cattle Parasitic Diseases: From Protozoa to Helminth Infections.

Molecules 2020 Nov 1;25(21). Epub 2020 Nov 1.

UMR 7042 CNRS-Université de Strasbourg-Université Haute-Alsace, Laboratoire d'Innovation Moléculaire et Applications (LIMA), Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France.

Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-β-d-glucopyranose 2,3,4,6-tetraacetato--derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites-protozoans, trematodes, and nematodes-was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic amastigotes and adult filarial and trematode worms.
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http://dx.doi.org/10.3390/molecules25215075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663263PMC
November 2020

The endosymbiont Wolbachia rebounds following antibiotic treatment.

PLoS Pathog 2020 07 8;16(7):e1008623. Epub 2020 Jul 8.

Dept. of Pharmaceutical Chemistry; University of California, San Francisco; San Francisco, California, United States of America.

Antibiotic treatment has emerged as a promising strategy to sterilize and kill filarial nematodes due to their dependence on their endosymbiotic bacteria, Wolbachia. Several studies have shown that novel and FDA-approved antibiotics are efficacious at depleting the filarial nematodes of their endosymbiont, thus reducing female fecundity. However, it remains unclear if antibiotics can permanently deplete Wolbachia and cause sterility for the lifespan of the adult worms. Concerns about resistance arising from mass drug administration necessitate a careful exploration of potential Wolbachia recrudescence. In the present study, we investigated the long-term effects of the FDA-approved antibiotic, rifampicin, in the Brugia pahangi jird model of infection. Initially, rifampicin treatment depleted Wolbachia in adult worms and simultaneously impaired female worm fecundity. However, during an 8-month washout period, Wolbachia titers rebounded and embryogenesis returned to normal. Genome sequence analyses of Wolbachia revealed that despite the population bottleneck and recovery, no genetic changes occurred that could account for the rebound. Clusters of densely packed Wolbachia within the worm's ovarian tissues were observed by confocal microscopy and remained in worms treated with rifampicin, suggesting that they may serve as privileged sites that allow Wolbachia to persist in worms while treated with antibiotic. To our knowledge, these clusters have not been previously described and may be the source of the Wolbachia rebound.
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http://dx.doi.org/10.1371/journal.ppat.1008623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371230PMC
July 2020

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells.

PLoS Negl Trop Dis 2020 05 26;14(5):e0007942. Epub 2020 May 26.

Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Efforts to identify new drugs for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen omics databases and drug databases from which new anthelmintic compounds might be identified. Here, a novel approach focused on integrating a pan-Nematoda multi-omics data targeted to a specific nematode organ system (the intestinal tract) with evidence-based filtering and chemogenomic screening was undertaken. Based on de novo computational target prioritization of the 3,564 conserved intestine genes in A. suum, exocytosis was identified as a high priority pathway, and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. 10 of 13 inhibitors were found to cause rapid immotility in A. suum L3 larvae, and five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.
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http://dx.doi.org/10.1371/journal.pntd.0007942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274465PMC
May 2020

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs.

ACS Infect Dis 2020 02 14;6(2):173-179. Epub 2020 Jan 14.

Anacor Pharmaceuticals, Inc. , 1020 E. Meadow Circle , Palo Alto , California 94303 , United States.

A series of benzimidazole-benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good activity against , a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series,  (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound was effective in killing , , and worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both and the positive control, flubendazole.
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http://dx.doi.org/10.1021/acsinfecdis.9b00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026885PMC
February 2020

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs.

ACS Infect Dis 2020 02 28;6(2):180-185. Epub 2020 Jan 28.

Anacor Pharmaceuticals, Inc. , 1020 E. Meadow Circle , Palo Alto , California 94303 , United States.

The optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against , a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.
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http://dx.doi.org/10.1021/acsinfecdis.9b00397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026882PMC
February 2020

Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models.

Int J Parasitol Drugs Drug Resist 2020 04 10;12:18-27. Epub 2019 Dec 10.

Dept. of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.

The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16-18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10-14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days.
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http://dx.doi.org/10.1016/j.ijpddr.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931063PMC
April 2020

Chagas Disease Serological Test Performance in U.S. Blood Donor Specimens.

J Clin Microbiol 2019 12 22;57(12). Epub 2019 Nov 22.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.

Chagas disease affects an estimated 300,000 individuals in the United States. Diagnosis in the chronic phase requires positive results from two different IgG serological tests. Three enzyme-linked immunosorbent assays (ELISAs) (Hemagen, Ortho, and Wiener) and one rapid test (InBios) are FDA cleared, but comparative data in U.S. populations are sparse. We evaluated 500 seropositive and 300 seronegative blood donor plasma samples. Country of birth was known for 255 seropositive specimens, which were grouped into regions as follows: Mexico ( = 94), Central America ( = 88), and South America ( = 73). Specimens were tested by the four FDA-cleared IgG serological assays. Test performance was evaluated by two comparators and latent class analysis. InBios had the highest sensitivity (97.4% to 99.3%) but the lowest specificity (87.5% to 92.3%). Hemagen had the lowest sensitivity (88.0% to 92.0%) but high specificity (99.0% to 100.0%). The level of sensitivity was intermediate for Ortho (92.4% to 96.5%) and Wiener (94.0% to 97.1%); both had high specificity (98.8% to 100.0% and 96.7% to 99.3%, respectively). The levels of antibody reactivity and clinical sensitivity were lowest in donors from Mexico, intermediate in those from Central America, and highest in those from South America. Our findings provide an initial evidence base to improve laboratory diagnosis of Chagas disease in the United States. The best current testing algorithm would employ a high-sensitivity screening test followed by a high-specificity confirmatory test.
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http://dx.doi.org/10.1128/JCM.01217-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879282PMC
December 2019

Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics.

Sci Rep 2019 06 24;9(1):9085. Epub 2019 Jun 24.

McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, Missouri, 63108, USA.

Targeting chokepoint enzymes in metabolic pathways has led to new drugs for cancers, autoimmune disorders and infectious diseases. This is also a cornerstone approach for discovery and development of anthelmintics against nematode and flatworm parasites. Here, we performed omics-driven knowledge-based identification of chokepoint enzymes as anthelmintic targets. We prioritized 10 of 186 phylogenetically conserved chokepoint enzymes and undertook a target class repurposing approach to test and identify new small molecules with broad spectrum anthelmintic activity. First, we identified and tested 94 commercially available compounds using an in vitro phenotypic assay, and discovered 11 hits that inhibited nematode motility. Based on these findings, we performed chemogenomic screening and tested 32 additional compounds, identifying 6 more active hits. Overall, 6 intestinal (single-species), 5 potential pan-intestinal (whipworm and hookworm) and 6 pan-Phylum Nematoda (intestinal and filarial species) small molecule inhibitors were identified, including multiple azoles, Tadalafil and Torin-1. The active hit compounds targeted three different target classes in humans, which are involved in various pathways, including carbohydrate, amino acid and nucleotide metabolism. Last, using representative inhibitors from each target class, we demonstrated in vivo efficacy characterized by negative effects on parasite fecundity in hamsters infected with hookworms.
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http://dx.doi.org/10.1038/s41598-019-45548-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591293PMC
June 2019

Development of a preliminary in vitro drug screening assay based on a newly established culturing system for pre-adult fifth-stage Onchocerca volvulus worms.

PLoS Negl Trop Dis 2019 01 17;13(1):e0007108. Epub 2019 Jan 17.

Molecular Parasitology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.

Background: The human filarial parasite Onchocerca volvulus is the causative agent of onchocerciasis (river blindness). It causes blindness in 270,000 individuals with an additional 6.5 million suffering from severe skin pathologies. Current international control programs focus on the reduction of microfilaridermia by annually administering ivermectin for more than 20 years with the ultimate goal of blocking of transmission. The adult worms of O. volvulus can live within nodules for over 15 years and actively release microfilariae for the majority of their lifespan. Therefore, protracted treatment courses of ivermectin are required to block transmission and eventually eliminate the disease. To shorten the time to elimination of this disease, drugs that successfully target macrofilariae (adult parasites) are needed. Unfortunately, there is no small animal model for the infection that could be used for discovery and screening of drugs against adult O. volvulus parasites. Here, we present an in vitro culturing system that supports the growth and development of O. volvulus young adult worms from the third-stage (L3) infective stage.

Methodology/principal Findings: In this study we optimized the culturing system by testing several monolayer cell lines to support worm growth and development. We have shown that the optimized culturing system allows for the growth of the L3 worms to L5 and that the L5 mature into young adult worms. Moreover, these young O. volvulus worms were used in preliminary assays to test putative macrofilaricidal drugs and FDA-approved repurposed drugs.

Conclusion: The culture system we have established for O. volvulus young adult worms offers a promising new platform to advance drug discovery against the human filarial parasite, O. volvulus and thus supports the continuous pursuit for effective macrofilaricidal drugs. However, this in vitro culturing system will have to be further validated for reproducibility before it can be rolled out as a drug screen for decision making in macrofilaricide drug development programs.
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http://dx.doi.org/10.1371/journal.pntd.0007108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353222PMC
January 2019

Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi.

PLoS Negl Trop Dis 2019 01 16;13(1):e0006787. Epub 2019 Jan 16.

Dept. of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.

River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2-15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms.
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http://dx.doi.org/10.1371/journal.pntd.0006787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334909PMC
January 2019

Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics.

ACS Infect Dis 2018 07 14;4(7):1130-1145. Epub 2018 May 14.

McDonnell Genome Institute , Washington University School of Medicine , 4444 Forest Park Ave. , St. Louis , Missouri 63108 , United States.

The enormous prevalence of infections caused by parasitic nematodes worldwide, coupled to the rapid emergence of their resistance to commonly used anthelmintic drugs, presents an urgent need for the discovery of new drugs. Herein, we have identified several classes of small molecules with broad spectrum activity against these pathogens. Previously, we reported the identification of carnitine palmitoyltransferases (CPTs) as a representative class of enzymes as potential targets for metabolic chokepoint intervention that was elucidated from a combination of chemogenomic screening and experimental testing in nematodes. Expanding on these previous findings, we have discovered that several chemical classes of known small molecule inhibitors of mammalian CPTs have potent activity as anthelmintics. Cross-clade efficacy against a broad spectrum of adult parasitic nematodes was demonstrated for multiple compounds from different series. Several analogs of these initial hit compounds were designed and synthesized. The compounds we report represent a good starting point for further lead identification and optimization for development of new anthelmintic drugs with broad spectrum activity and a novel mechanism of action.
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http://dx.doi.org/10.1021/acsinfecdis.8b00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283408PMC
July 2018

Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.

PLoS Negl Trop Dis 2015 Feb 20;9(2):e0003534. Epub 2015 Feb 20.

Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America.

Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.
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http://dx.doi.org/10.1371/journal.pntd.0003534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336141PMC
February 2015

Effect of crude lipopolysaccharide from Escherichia coli O127:B8 on the amebocyte-producing organ of Biomphalaria glabrata (Mollusca).

Dev Comp Immunol 2011 Nov 19;35(11):1182-5. Epub 2011 Apr 19.

Department of Biology, University of San Francisco, San Francisco, CA 94117, USA.

Lipopolysaccharide (LPS) is a pathogen associated molecular pattern (PAMP) to which the internal defense system (IDS) of both vertebrates and invertebrates responds. We measured the mitotic response of the hematopoietic tissue of the schistosome-transmitting snail, Biomphalaria glabrata, to crude LPS from Escherichia coli 0127:B8. In a dose-response study, snails were injected with a range of concentrations of crude LPS, and mitotic figures were enumerated in histological sections of amebocyte-producing organ (APO) fixed at 24h post-injection (PI) following a 6h treatment with 0.1% colchicine. In APOs from Salvador strain snails, which are genetically resistant to infection with Schistosoma mansoni, LPS concentrations of 0.01 mg/ml and above triggered a large increase in mitotic activity, whereas in APOs from schistosome-susceptible NIH albino snails, concentrations of 0.1mg/ml elicited a much smaller, but statistically significant increase. A time course study, without colchicine treatment, revealed that in Salvador APOs the mitotic response to 0.1mg/ml occurred by 18 h PI, peaked at 24h, and returned to control levels by 72 h; NIH albino APOs showed no detectible response. When Salvador APOs were exposed to crude LPS in vitro, no increase in mitotic activity occurred, a result suggesting the possible requirement for a peripheral tissue or hemolymph factor. The increased cell proliferation induced by crude LPS represents a novel systemic response of an invertebrate IDS to one or more PAMPs from a Gram-negative bacterium.
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http://dx.doi.org/10.1016/j.dci.2011.03.032DOI Listing
November 2011
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