scholarly journals PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites

2016 ◽  
Vol 60 (5) ◽  
pp. 2858-2863 ◽  
Author(s):  
Anne-Marie Zeeman ◽  
Suresh B. Lakshminarayana ◽  
Nicole van der Werff ◽  
Els J. Klooster ◽  
Annemarie Voorberg-van der Wel ◽  
...  
Keyword(s):  
Drug Target ◽  
Rhesus Macaques ◽  
Secondary Infection ◽  
Pharmacokinetic Data ◽  
Radical Cure ◽  
Plasma Exposure ◽  
Content Type ◽  
Plasmodium Cynomolgi

ABSTRACTTwoPlasmodiumPI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected forin vivotesting as causal prophylactic and radical-cure agents forPlasmodium cynomolgisporozoite-infected rhesus macaques, based on theirin vitroactivity against liver stages. Animals were infected withP. cynomolgisporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on ourin vitrodata. These findings indicate thatPlasmodiumPI4K is a potential drug target for malaria prophylaxis but not radical cure. Longerin vitroculture systems will be required to assess these compounds' activity on established hypnozoites and predict radical curein vivo.

scholarly journals Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Pattaraporn Vanachayangkul ◽  
Rawiwan Im-erbsin ◽  
Anchalee Tungtaeng ◽  
Chanikarn Kodchakorn ◽  
Alison Roth ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
High Dose ◽  
Radical Cure ◽  
The Novel ◽  
Liver Stage ◽  
Content Type ◽  
Plasmodium Cynomolgi ◽  
Stage Development ◽  
Pharmacokinetic Drug

ABSTRACT Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 μM) and hypnozoites (IC50, 29.24 μM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.

scholarly journals Structure-Activity Relationships of a Series of Echinocandins and the Discovery of CD101, a Highly Stable and Soluble Echinocandin with Distinctive Pharmacokinetic Properties

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Kenneth D. James ◽  
Christopher P. Laudeman ◽  
Navdeep B. Malkar ◽  
Radha Krishnan ◽  
Karen Polowy
Keyword(s):  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Activity Data ◽  
Content Type ◽  
Structure Activity Relationships ◽  
First Line Therapy ◽  
Structure Activity ◽  
Pharmacokinetic Properties

ABSTRACT Echinocandins are a first-line therapy for candidemia and invasive candidiasis. They are generally safe with few drug interactions, but the stability and pharmacokinetic properties of currently approved echinocandins are such that each was developed for daily intravenous infusion. We sought to discover a novel echinocandin with properties that would enable more flexible dosing regimens, alternate routes of delivery, and expanded utility. Derivatives of known echinocandin scaffolds were generated, and an iterative process of design and screening led to the discovery of CD101, a novel echinocandin that has since demonstrated improved chemical stability and pharmacokinetics. Here, we report the structure-activity relationships (including preclinical efficacy and pharmacokinetic data) for the series of echinocandin analogs from which CD101 was selected. In a mouse model of disseminated candidiasis, the test compounds displayed clear dose responses and were generally associated with lower fungal burdens than that of anidulafungin. Single-dose pharmacokinetic studies in beagle dogs revealed a wide disparity in the half-lives and volumes of distribution, with one compound (now known as CD101) displaying a half-life that is nearly 5-fold longer than that of anidulafungin (53.1 h versus 11.6 h, respectively). In vitro activity data against panels of Candida spp. and Aspergillus spp. demonstrated that CD101 behaved similarly to approved echinocandins in terms of potency and spectrum of activity, suggesting that the improved efficacy observed in vivo for CD101 is a result of features beyond the antifungal potency inherent to the molecule. Factors that potentially contribute to the improved in vivo efficacy of CD101 are discussed.

scholarly journals Interferon-Stimulated Gene (ISG)-Expression Screening Reveals the Specific Antibunyaviral Activity of ISG20

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Junjie Feng ◽  
Arthur Wickenhagen ◽  
Matthew L. Turnbull ◽  
Veronica V. Rezelj ◽  
Felix Kreher ◽  
...  
Keyword(s):  
Viral Infections ◽  
Rhesus Macaques ◽  
Type I ◽  
Emerging Viruses ◽  
Content Type ◽  
Expression Screening ◽  
Interferon Stimulated Genes ◽  
Life Threatening

ABSTRACT Bunyaviruses pose a significant threat to human health, prosperity, and food security. In response to viral infections, interferons (IFNs) upregulate the expression of hundreds of interferon-stimulated genes (ISGs), whose cumulative action can potently inhibit the replication of bunyaviruses. We used a flow cytometry-based method to screen the ability of ∼500 unique ISGs from humans and rhesus macaques to inhibit the replication of Bunyamwera orthobunyavirus (BUNV), the prototype of both the Peribunyaviridae family and the Bunyavirales order. Candidates possessing antibunyaviral activity were further examined using a panel of divergent bunyaviruses. Interestingly, one candidate, ISG20, exhibited potent antibunyaviral activity against most viruses examined from the Peribunyaviridae , Hantaviridae , and Nairoviridae families, whereas phleboviruses ( Phenuiviridae ) largely escaped inhibition. Similar to the case against other viruses known to be targeted by ISG20, the antibunyaviral activity of ISG20 is dependent upon its functional RNase activity. Through use of an infectious virus-like particle (VLP) assay (based on the BUNV minigenome system), we confirmed that gene expression from all 3 viral segments is strongly inhibited by ISG20. Using in vitro evolution, we generated a substantially ISG20-resistant BUNV and mapped the determinants of ISG20 sensitivity/resistance. Taking all the data together, we report that ISG20 is a broad and potent antibunyaviral factor but that some bunyaviruses are remarkably ISG20 resistant. Thus, ISG20 sensitivity/resistance may influence the pathogenesis of bunyaviruses, many of which are emerging viruses of clinical or veterinary significance. IMPORTANCE There are hundreds of bunyaviruses, many of which cause life-threatening acute diseases in humans and livestock. The interferon (IFN) system is a key component of innate immunity, and type I IFNs limit bunyaviral propagation both in vitro and in vivo . Type I IFN signaling results in the upregulation of hundreds of IFN-stimulated genes (ISGs), whose concerted action generates an “antiviral state.” Although IFNs are critical in limiting bunyaviral replication and pathogenesis, much is still unknown about which ISGs inhibit bunyaviruses. Using ISG-expression screening, we examined the ability of ∼500 unique ISGs to inhibit Bunyamwera orthobunyavirus (BUNV), the prototypical bunyavirus. Using this approach, we identified ISG20, an interferon-stimulated exonuclease, as a potent inhibitor of BUNV. Interestingly, ISG20 possesses highly selective antibunyaviral activity, with multiple bunyaviruses being potently inhibited while some largely escape inhibition. We speculate that the ability of some bunyaviruses to escape ISG20 may influence their pathogenesis.

scholarly journals Safety, pharmacokinetics, and liver-stage Plasmodium cynomolgi effect of high-dose ivermectin and chloroquine in Rhesus Macaques

2020 ◽  
Author(s):  
Pattaraporn Vanachayangkul ◽  
Rawiwan Im-erbsin ◽  
Anchalee Tungtaeng ◽  
Chanikarn Kodchakorn ◽  
Alison Roth ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Rhesus Macaques ◽  
High Dose ◽  
Radical Cure ◽  
The Novel ◽  
Liver Stage ◽  
Plasmodium Cynomolgi ◽  
Stage Development ◽  
Pharmacokinetic Drug

AbstractPreviously, ivermectin (1–10 mg/kg) was shown to inhibit liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (IC50 = 10.42 μM) and hypnozoites (IC50 = 29.24 μM) in primary macaque hepatocytes when administered in high-dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for seven consecutive days was evaluated for prophylaxis or radical cure of Plasmodium cynomolgi liver-stages in Rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for seven days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in vitro. Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.

scholarly journals Antitrypanosomal Activity of Fexinidazole, a New Oral Nitroimidazole Drug Candidate for Treatment of Sleeping Sickness

2011 ◽  
Vol 55 (12) ◽  
pp. 5602-5608 ◽  
Author(s):  
Marcel Kaiser ◽  
Michael A. Bray ◽  
Monica Cal ◽  
Bernadette Bourdin Trunz ◽  
Els Torreele ◽  
...  
Keyword(s):  
Oral Treatment ◽  
Sleeping Sickness ◽  
Drug Candidate ◽  
Pharmacokinetic Data ◽  
Parent Molecule ◽  
Content Type ◽  
Trypanocidal Activity ◽  
Parasite Strains

ABSTRACTFexinidazole is a 5-nitroimidazole drug currently in clinical development for the treatment of human sleeping sickness (human African trypanosomiasis [HAT]), caused by infection with species of the protozoan parasiteTrypanosoma brucei. The compound and its two principal metabolites, sulfoxide and sulfone, have been assessed for their ability to kill a range ofT. bruceiparasite strainsin vitroand to cure both acute and chronic HAT disease models in the mouse. The parent molecule and both metabolites have shown trypanocidal activityin vitroin the 0.7-to-3.3 μM (0.2-to-0.9 μg/ml) range against all parasite strains tested.In vivo, fexinidazole is orally effective in curing both acute and chronic diseases in the mouse at doses of 100 mg/kg of body weight/day for 4 days and 200 mg/kg/day for 5 days, respectively. Pharmacokinetic data indicate that it is likely that the sulfoxide and sulfone metabolites provide most, if not all, of thein vivokilling activity. Fexinidazole and its metabolites require up to 48 h exposure in order to induce maximal trypanocidal efficacyin vitro. The parent drug and its metabolites show noin vitrocross-reactivity in terms of trypanocidal activity with either themselves or other known trypanocidal drugs in use in humans. Thein vitroandin vivoantitrypanosomal activities of fexinidazole and its two principal metabolites provide evidence that the compound has the potential to be an effective oral treatment for both theT. b. gambienseandT. b. rhodesienseforms of human sleeping sickness and both stages of the disease.

scholarly journals KAI407, a Potent Non-8-Aminoquinoline Compound That Kills Plasmodium cynomolgi Early Dormant Liver Stage ParasitesIn Vitro

2013 ◽  
Vol 58 (3) ◽  
pp. 1586-1595 ◽  
Author(s):  
Anne-Marie Zeeman ◽  
Sandra M. van Amsterdam ◽  
Case W. McNamara ◽  
Annemarie Voorberg-van der Wel ◽  
Els J. Klooster ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Inhibitory Concentration ◽  
Radical Cure ◽  
Malaria Prophylaxis ◽  
Activity Profile ◽  
Liver Stage ◽  
Content Type ◽  
Plasmodium Cynomolgi ◽  
Malaria Eradication

ABSTRACTPreventing relapses ofPlasmodium vivaxmalaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay ofin vitro-cultured hypnozoite forms ofPlasmodium cynomolgi(an excellent and accessible model forPlasmodium vivax). In this assay, primary rhesus hepatocytes are infected withP. cynomolgisporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class forP. vivaxmalaria prophylaxis and potentially a radical cure.

scholarly journals Homology Modeling of NAD+-Dependent DNA Ligase of the Wolbachia Endosymbiont of Brugia malayi and Its Drug Target Potential Using Dispiro-Cycloalkanones

2015 ◽  
Vol 59 (7) ◽  
pp. 3736-3747 ◽  
Author(s):  
Nidhi Shrivastava ◽  
Jeetendra K. Nag ◽  
Jyoti Pandey ◽  
Rama Pati Tripathi ◽  
Priyanka Shah ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Drug Target ◽  
Brugia Malayi ◽  
Great Promise ◽  
Dna Ligase ◽  
Content Type ◽  
T4 Dna Ligase ◽  
Filarial Nematodes

ABSTRACTLymphatic filarial nematodes maintain a mutualistic relationship with the endosymbiontWolbachia. Depletion ofWolbachiaproduces profound defects in nematode development, fertility, and viability and thus has great promise as a novel approach for treating filarial diseases. NAD+-dependent DNA ligase is an essential enzyme of DNA replication, repair, and recombination. Therefore, in the present study, the antifilarial drug target potential of the NAD+-dependent DNA ligase of theWolbachiasymbiont ofBrugia malayi(wBm-LigA) was investigated using dispiro-cycloalkanone compounds. Dispiro-cycloalkanone specifically inhibited the nick-closing and cohesive-end ligation activities of the enzyme without inhibiting human or T4 DNA ligase. The mode of inhibition was competitive with the NAD+cofactor. Docking studies also revealed the interaction of these compounds with the active site of the target enzyme. The adverse effects of these inhibitors were observed on adult and microfilarial stages ofB. malayiin vitro, and the most active compounds were further monitoredin vivoin jirds and mastomys rodent models. Compounds 1, 2, and 5 had severe adverse effectsin vitroon the motility of both adult worms and microfilariae at low concentrations. Compound 2 was the best inhibitor, with the lowest 50% inhibitory concentration (IC50) (1.02 μM), followed by compound 5 (IC50, 2.3 μM) and compound 1 (IC50, 2.9 μM). These compounds also exhibited the same adverse effect on adult worms and microfilariaein vivo(P< 0.05). These compounds also tremendously reduced the wolbachial load, as evident by quantitative real-time PCR (P< 0.05).wBm-LigA thus shows great promise as an antifilarial drug target, and dispiro-cycloalkanone compounds show great promise as antifilarial lead candidates.

scholarly journals UCT943, a Next-GenerationPlasmodium falciparumPI4K Inhibitor Preclinical Candidate for the Treatment of Malaria

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Christel Brunschwig ◽  
Nina Lawrence ◽  
Dale Taylor ◽  
Efrem Abay ◽  
Mathew Njoroge ◽  
...  
Keyword(s):  
Intrinsic Clearance ◽  
Drug Candidate ◽  
Radical Cure ◽  
Next Generation ◽  
Parasite Life Cycle ◽  
Asexual Blood Stage ◽  
Content Type ◽  
Human Dose

ABSTRACTThe 2-aminopyridine MMV048 was the first drug candidate inhibitingPlasmodiumphosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistantPlasmodium falciparumandPlasmodium vivaxclinical isolates. Excellentin vitroantiplasmodial activity translated into high efficacy inPlasmodium bergheiand humanizedP. falciparumNOD-scid IL-2Rγnullmouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderatein vivointrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generationPlasmodiumPI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.

scholarly journals Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa

2019 ◽  
Vol 202 (8) ◽  
Author(s):  
Courtney E. Price ◽  
Dustin G. Brown ◽  
Dominique H. Limoli ◽  
Vanessa V. Phelan ◽  
George A. O’Toole
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Physical Space ◽  
Late Time ◽  
Protective Effects ◽  
Content Type ◽  
Alginate Production ◽  
The Impact

ABSTRACT Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are monoinfected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can coexist with S. aureus in vitro due to the transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here, we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm coculture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to the transcriptional downregulation of pvdA, a gene required for the production of the iron-scavenging siderophore pyoverdine as well as the downregulation of the PQS (Pseudomonas quinolone signal) (2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that coculture of mucoid P. aeruginosa with nonmucoid P. aeruginosa strains can mitigate the killing of S. aureus by the nonmucoid strain of P. aeruginosa, indicating that the mechanism that we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner. IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients coinfected by both species. Such coinfected individuals have worse outcomes than monoinfected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus coexistence, despite evidence that P. aeruginosa kills S. aureus when these organisms are cocultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to coexist in proximal physical space, will lead to better-informed treatments for chronic polymicrobial infections.

scholarly journals In Vitro Synergy and In Vivo Activity of Tigecycline-Ciprofloxacin Combination Therapy against Vibrio vulnificus Sepsis

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Seong Eun Kim ◽  
Hee Kyung Kim ◽  
Su-Mi Choi ◽  
Yohan Yu ◽  
Uh Jin Kim ◽  
...  
Keyword(s):  
Survival Rate ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Vibrio Vulnificus ◽  
Antibiotic Regimen ◽  
Content Type ◽  
Time Kill

ABSTRACT The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline-ciprofloxacin may be an effective novel antibiotic regimen for V. vulnificus sepsis.

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