Enhancement in therapeutic efficacy of miltefosine in combination with synthetic bacterial lipopeptide, Pam3Cys against experimental Visceral Leishmaniasis

Shakya, Nishi; Sane, Shraddha A.; Vishwakarma, Preeti; Gupta, Suman

doi:10.1016/j.exppara.2012.05.007

Cited by 29 publications

(54 citation statements)

References 23 publications

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“…Combination therapy, which uses a mixture of two drugs, has been extensively used to treat many infectious diseases . More recently, experimental evidence is gaining importance with regards to combination therapy in controlling bacterial infections as well .…”

Section: Discussionmentioning

confidence: 99%

“…These three cocktails were able to bring about c.10 000-fold reduction in the bacterial titres of all six bacteria tested, which was at least 10-to 100-fold higher than the action of individual peptides acting alone. Combination therapy, which uses a mixture of two drugs, has been extensively used to treat many infectious diseases [8,27]. More recently, experimental evidence is gaining importance with regards to combination therapy in controlling bacterial infections as well [23,25,28,29].…”

Section: Discussionmentioning

confidence: 99%

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Enhanced antimicrobial activity of peptide-cocktails against common bacterial contaminants of ex vivo stored platelets

Mohan

Rao

Gao

et al. 2014

Clinical Microbiology and Infection

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Bacterial contamination of blood components such as ex vivo-stored platelets is a major safety risk in transfusion medicine. We have recently shown that synthetic antimicrobial peptides named PD1-PD4 derived from the thrombin-induced human platelet-derived antimicrobial proteins, and repeats of Arg-Trp (RW1-RW5) demonstrate microbicidal activity against selected bacteria and viruses. In the present study, we selected PD3, PD4, RW2, RW3 and RW4 and evaluated each individual peptide and their various combinations to see whether the cocktail regimen enhances the antimicrobial activity above and over the individual peptides. Stored platelet or plasma samples spiked with known titres of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Bacillus cereus were treated with either individual peptides or with peptides in various combinations. Analyses revealed that individual peptides show moderate microbicidal activity (10- to 100-fold reduction) against the tested bacteria relative to their combined regimen. The peptide combinations (RW2 + RW4, RW2 + RW3 + RW4 and PD4 + RW3 + RW4) on the other hand enhanced the microbicidal activity (c.10 000-fold reduction) and revealed a minimal inhibitory concentration of 5 μM. Time-kill kinetics indicated that these three peptide combinations exhibited enhanced antimicrobial activity bringing about a 100-fold reduction of bacterial titres within 20 min of incubation. The present study therefore demonstrates the synergistic effect of antimicrobial peptides when used in combinations and provides a proof-of-concept of its potential application as a molecular tool towards pathogen reduction and further extends the possibility of using peptide combinatorial therapeutics as broad-spectrum antibiotics or as alternatives to combat drug-resistant bacteria.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhanced antimicrobial activity of peptide-cocktails against common bacterial contaminants of ex vivo stored platelets

Mohan

Rao

Gao

et al. 2014

Clinical Microbiology and Infection

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“…Using lower doses of miltefosine in combination with Pam3Cys (an immunomodulator synthetic bacterial lipopeptide (BLP) and TLR-2/1 ligand) in a BALB/c mouse model of VL, Shakya et al (137) demonstrated significantly enhanced parasitic inhibition and Th1 cytokine production and an increased phagocytosis index. Another study, conducted by Karmakar et al (138), demonstrated the interactions between a TLR ligand and invariant natural killer T (iNKT) cell activation as immunotherapy in VL.…”

Section: Recents Advances In Murine Modelsmentioning

confidence: 99%

Immunotherapy and Immunochemotherapy in Visceral Leishmaniasis: Promising Treatments for this Neglected Disease

et al. 2014

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Leishmaniasis has several clinical forms: self-healing or chronic cutaneous leishmaniasis or post-kala-azar dermal leishmaniasis; mucosal leishmaniasis; visceral leishmaniasis (VL), which is fatal if left untreated. The epidemiology and clinical features of VL vary greatly due to the interaction of multiple factors including parasite strains, vectors, host genetics, and the environment. Human immunodeficiency virus infection augments the severity of VL increasing the risk of developing active disease by 100–2320 times. An effective vaccine for humans is not yet available. Resistance to chemotherapy is a growing problem in many regions, and the costs associated with drug identification and development, make commercial production for leishmaniasis, unattractive. The toxicity of currently drugs, their long treatment course, and limited efficacy are significant concerns. For cutaneous disease, many studies have shown promising results with immunotherapy/immunochemotherapy, aimed to modulate and activate the immune response to obtain a therapeutic cure. Nowadays, the focus of many groups centers on treating canine VL by using vaccines and immunomodulators with or without chemotherapy. In human disease, the use of cytokines like interferon-γ associated with pentavalent antimonials demonstrated promising results in patients that did not respond to conventional treatment. In mice, immunomodulation based on monoclonal antibodies to remove endogenous immunosuppressive cytokines (interleukin-10) or block their receptors, antigen-pulsed syngeneic dendritic cells, or biological products like Pam3Cys (TLR ligand) has already been shown as a prospective treatment of the disease. This review addresses VL treatment, particularly immunotherapy and/or immunochemotherapy as an alternative to conventional drug treatment in experimental models, canine VL, and human disease.

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“…In this context, the murine models have been employed using different strategies such as synthetic bacterial lipopeptide (Pam3cys), monoclonal antibodies (mAbs) against cytokine receptors or cytokines, dendritic cell-based treatment, and vaccines. All of these strategies are combined with chemotherapy using low dose or short course of an effective conventional drug or new candidates (16–20). Dogs are considered one of the most important models for VL studies including vaccines and treatment tests and more recently has become even more relevant for the evaluation of immunotherapy and immunochemotherapy protocols.…”

Section: Introductionmentioning

confidence: 99%

A Vaccine Therapy for Canine Visceral Leishmaniasis Promoted Significant Improvement of Clinical and Immune Status with Reduction in Parasite Burden

et al. 2017

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Herein, we evaluated the treatment strategy employing a therapeutic heterologous vaccine composed of antigens of Leishmania braziliensis associated with MPL adjuvant (LBMPL vaccine) for visceral leishmaniasis (VL) in symptomatic dogs naturally infected by Leishmania infantum. Sixteen dogs received immunotherapy with MPL adjuvant (n = 6) or with a vaccine composed of antigens of L. braziliensis associated with MPL (LBMPL vaccine therapy, n = 10). Dogs were submitted to an immunotherapeutic scheme consisting of 3 series composed of 10 subcutaneous doses with 10-day interval between each series. The animals were evaluated before (T0) and 90 days after treatment (T90) for their biochemical/hematological, immunological, clinical, and parasitological variables. Our major results showed that the vaccine therapy with LBMPL was able to restore and normalize main biochemical (urea, AST, ALP, and bilirubin) and hematological (erythrocytes, hemoglobin, hematocrit, and platelets) parameters. In addition, in an ex vivo analysis using flow cytometry, dogs treated with LBMPL vaccine showed increased CD3

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Enhancement in therapeutic efficacy of miltefosine in combination with synthetic bacterial lipopeptide, Pam3Cys against experimental Visceral Leishmaniasis

Cited by 29 publications

References 23 publications

Enhanced antimicrobial activity of peptide-cocktails against common bacterial contaminants of ex vivo stored platelets

Enhanced antimicrobial activity of peptide-cocktails against common bacterial contaminants of ex vivo stored platelets

Immunotherapy and Immunochemotherapy in Visceral Leishmaniasis: Promising Treatments for this Neglected Disease

A Vaccine Therapy for Canine Visceral Leishmaniasis Promoted Significant Improvement of Clinical and Immune Status with Reduction in Parasite Burden

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