sirolimus and Bacterial-Infections

Infectious diseases are a major cause of morbidity and mortality worldwide, exacerbated by increasing antibiotic resistance in many bacterial species. The development of drugs with new modes of action is essential. A leading strategy is antivirulence, with the aim to target bacterial proteins that are important in disease causation and progression but do not affect growth, resulting in reduced selective pressure for resistance. Immunophilins, a superfamily of peptidyl-prolyl

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Bacterial Proteins; Drug Delivery Systems; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary

FK506-binding proteins (FKBPs) contain a domain with peptidyl-prolyl-cis/trans-isomerase (PPIase) activity and bind the immunosuppressive drugs FK506 and rapamycin. FKBPs belong to the immunophilin family and are found in eukaryotes and bacteria.. In this review we describe two major groups of bacterial virulence-associated FKBPs, the trigger factor and Mip-like PPIases. Moreover, we discuss the contribution of host FKBPs in bacterial infection processes.. Since PPIases are regarded as alternative antiinfective drug targets we highlight current research strategies utilizing pipecolinic acid and cycloheximide derivatives as well as substrate based inhibitors.. The current research strategies suggest a beneficial synergism of drug development and basic research. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.

Topics: Animals; Bacteria; Bacterial Infections; Bacterial Proteins; Cycloheximide; Humans; Peptidylprolyl Isomerase; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins; Virulence Factors

Macrophage is a key cell of immune system, it participates in antiviral, antimicrobial and antitumor defense of the organism, also in regeneration and reparation of tissues. Macrophage coordinates functioning of immune system, participates in tumor growth progression. The process of inflammation consists of two stages. Cytotoxical potential of immunocompetent cells will be realized in the first stage, to avoid a bacterial infection. The second stage of inflammatory process is associated with reparation and regeneration. During inflammation, according it stages, macrophages change functional state, switching from cytotoxical M1 to M2, that associated with reparation. We suppose, that rapamysin, a suppressor of mTOR, causes completely different effects on tumor associated macrophages and cells of microglia. Rapamycin transforms tissue macrophages into M1 phenotype, promoting the tumor regression. While in microglial cells of the central nervous system it induces transformation into M2 phenotype, facilitating the course of the neurodegenerative disease and slowing down the aging.

Topics: Animals; Bacterial Infections; Humans; Macrophages; Neoplasms; Neurodegenerative Diseases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Virus Diseases

The immune system protects the host from pathogenic microbes, but tight regulation of the evoked response is requisite to limit bystander damage. The interleukin (IL)-10 family of cytokines, composed of 9 members: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and 3 distantly related members, IL-28A, IL-28B, and IL-29, plays a central role in this regulation. IL-10 family cytokines emerged before the adaptive immune response and elicit diverse host defense mechanisms, especially from epithelial cells during an infection. IL-10 family cytokines are also essential for maintenance and integrity of tissue epithelial layers. These cytokines promote innate immune responses from tissue epithelia that limit the damage caused by both viral and bacterial infections. They also facilitate tissue healing after infection/inflammation. In this regard, IL-10 suppresses pro-inflammatory responses, limiting tissue disruption resulting from an inflammatory response. Thus, a central functional theme of IL-10 family cytokines is their role in tissue protection. This review focuses on IL-10, the founding member of this family of cytokines, and integrates recent data on the function and regulation of IL-10 during bacterial infections. Emphasis is placed on the role of IL-10 in Pseudomonas aeruginosa keratitis and the subsequent infectious/inflammatory processes evoked.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Eye Infections, Bacterial; Humans; Interleukin-10; Keratitis; Pseudomonas aeruginosa; Pseudomonas Infections; Sirolimus

Autophagy is one of the intracellular systems that is responsible for protein trafficking (degradation/recycling) in eukaryotic cells. This ubiquitous process contributes to cytosolic homeostasis, but its deregulation is often associated with various pathologies, including neurodegenerative diseases and cancer and pathologies with an altered inflammatory response. This review provides an overview of autophagy and discusses its regulation, function and future therapeutic possibilities, with a focus on the role of autophagy in inflammation.

Topics: Animals; Apoptosis; Autophagy; Bacterial Infections; Homeostasis; Humans; Inflammation; Lysosomes; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Proteins; Sirolimus; Stress, Physiological; Virus Diseases

Topics: Animals; Anti-Infective Agents; Antiviral Agents; B-Lymphocytes; Bacterial Infections; Cyclosporine; HIV; Humans; Immunosuppressive Agents; Parasitic Diseases; Polyenes; Sirolimus; T-Lymphocytes; Tacrolimus; Virus Diseases

Topics: Anticholesteremic Agents; Bacterial Infections; Cholesterol; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Patient Selection; Postoperative Complications; Prednisone; Sirolimus; Time Factors; Transplantation, Homologous; Treatment Failure; Treatment Outcome; Triglycerides

Sirolimus is increasingly investigated as a new targeted therapy in pediatric populations. To date, population pharmacokinetic (PK) studies have identified several factors that explain in part the large between-patient variability in sirolimus PK. However, within-patient variability in sirolimus PK is not well documented. This study presents examples of model-based PK-guided dosing of sirolimus in children with acute lymphoblastic leukemia (ALL), where patients experienced significant changes in sirolimus blood concentrations due to infection and food intake during the treatment period.. Three patients were enrolled in this study. Two patients achieved target concentration attainment with the PK model-informed loading dose on day 1 of sirolimus treatment. Subsequent unexpected high sirolimus concentrations were observed in two patients, where patients had flulike symptoms such as fever and cough. A sudden decrease in sirolimus concentrations was observed in one patient after switching sirolimus administration from the fed to the fasting state.. This study highlights within-patient fluctuations in sirolimus concentrations associated with intercurrent infection and with changes in diet. These findings highlight the challenge of maintaining a target sirolimus concentration as a patient's clinical status changes, and the benefit of intensive monitoring of therapeutic drug levels in children treated with sirolimus. Intra-patient alternations in sirolimus PK due to similar disease/food interactions may be relevant in pediatric patients treated with sirolimus for other disease indications.

Topics: Adolescent; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Bacterial Infections; Child, Preschool; Female; Food-Drug Interactions; Humans; Male; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Sirolimus; Voriconazole

Neutrophils are highly specialized innate immune effector cells that evolved for antimicrobial host defense. In response to inflammatory stimuli and pathogens, they form neutrophil extracellular traps (NETs), which capture and kill extracellular microbes. Deficient NET formation predisposes humans to severe infection, but, paradoxically, dysregulated NET formation contributes to inflammatory vascular injury and tissue damage. The molecular pathways and signaling mechanisms that control NET formation remain largely uncharacterized. Using primary human neutrophils and genetically manipulated myeloid leukocytes differentiated to surrogate neutrophils, we found that mammalian target of rapamycin (mTOR) regulates NET formation by posttranscriptional control of expression of hypoxia-inducible factor 1 α (HIF-1α), a critical modulator of antimicrobial defenses. Next-generation RNA sequencing, assays of mRNA and protein expression, and analysis of NET deployment by live cell imaging and quantitative histone release showed that mTOR controls NET formation and translation of HIF-1α mRNA in response to lipopolysaccharide. Pharmacologic and genetic knockdown of HIF-1α expression and activity inhibited NET deployment, and inhibition of mTOR and HIF-1α inhibited NET-mediated extracellular bacterial killing. Our studies define a pathway to NET formation involving 2 master regulators of immune cell function and identify potential points of molecular intervention in strategies to modify NETs in disease.

Topics: Adult; Bacteria; Bacterial Infections; Base Pairing; Base Sequence; Cells, Cultured; Extracellular Space; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunosuppressive Agents; Lipopolysaccharides; Molecular Sequence Data; Neutrophils; Nucleic Acid Conformation; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

There is an urgent need for the design and development of new and selective drugs for the treatment of malaria and bacterial infections as these pathogens are developing resistance to presently available therapies. Malaria is a life threatening disease in many countries and responsible for almost one million deaths annually. In particular, drug-resistant malarial parasites are hindering effective control of malaria and prompting to find novel druggable targets and develop compounds with mechanism of action different from the conventional drugs. In this quest, efforts were made to determine three-dimensional structures of Plasmodium falciparum and Plasmodium vivax FK506 binding proteins which bind the macrolides (FK506 and rapamycin) and also demonstrate peptidylprolyl cis-trans isomerase activity in a similar manner as human FKBP12. Previous studies revealed that the immunosuppressive drug FK506 exhibits potential anti-malarial activity by binding FK506 binding domains (FKBD). This review focuses on three different types of FK506 binding proteins/domains in pathogens, their structural characteristics and biological roles. Binding ability of these proteins with the macrolides has opened new possibilities to develop selective inhibitors for these novel targets to combat the life threatening infections.

Topics: Bacterial Infections; Drug Delivery Systems; Humans; Immunosuppressive Agents; Malaria; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins

Rapamycin, an inhibitor of mammalian target of rapamycin kinase, is a potent immunosuppressive drug that also displays antineoplastic properties and expands regulatory T cells. Steroid-refractory acute graft-versus-host disease (GVHD) remains a significant cause of mortality after allogeneic stem-cell transplantation and therapeutic options are not codified. We retrospectively evaluated the role of rapamycin in this setting.. In this retrospective single-center study, 22 patients were identified, from October 2004 to February 2008, as having received rapamycin for acute GVHD refractory to one or more lines of treatment. We analyzed the efficacy and tolerance of rapamycin and the outcome of these 22 patients in this setting.. Rapamycin resulted in a rapid and sustained complete remission of GVHD in 72% of heavily pretreated patients. Cytopenias were frequent but did not require treatment interruption. Thrombotic microangiopathy developed in 36% of patients when rapamycin was associated with calcineurin inhibitors and frequently resolved after interruption of one or both drugs. At a median follow-up of 13 months, overall survival was 41%. Previous treatment with high-dose steroid pulses was associated with a worse outcome (survival 12% vs. 69%). The major cause of death was infectious complications (77%).. Despite a small and heterogeneous population of patients, these results are encouraging and provide a rationale for prospective studies that use rapamycin in steroid-refractory acute GVHD as a second- or third-line agent.

Topics: Adolescent; Adult; Bacterial Infections; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Retrospective Studies; Sirolimus; Survival Rate; Survivors; Transplantation, Homologous; Treatment Outcome; Young Adult

An important side effect of sirolimus, a drug often used in organ transplantation, is pulmonary toxicity.. We present five kidney transplant patients who developed this toxicity associated with sirolimus. All underwent chest radiography computed tomography, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL), microbiological studies of the bronchial aspirate, blood, and sputum, and cytomegalovirus (CMV) polymerase chain reaction (PCR) in blood as well as two had transbronchial biopsies.. All five were men of mean age 54.8 +/- 10.3 years. In two sirolimus formed part of de novo therapy, and three were converted from calcineurin inhibitors. The mean treatment time was 16.6 +/- 13.7 months, with trough levels of 11.3 +/- 3 ng/mL. The patients presented with fever, cough, dyspnea, anemia, and dyslipidemia. The radiological pattern was diffuse alveolointerstitial (n = 2), or bilateral basal interstitial (n = 2), or bilateral basal alveolar (n = 1). The cell count in the BAL was 95% to 99% macrophages. In two patients cultures for bacteria were positive: Hemophilus and Pseudomonas. Tests for fungi, mycobacteria, pneumocystis, and legionella, as well as PCR for CMV were all negative. Transbronchial biopsy yielded insufficient material in one patient and a deposit of fibrinoid material and nonnecrotizing granuloma in the other. Antibacterial therapy was started, three with cotrimoxazole and two with ganciclovir, with no response. The respiratory symptoms improved after withdrawal of sirolimus (mean, 2.4 +/- 1.5 days). The mean hospital stay was 19.8 +/- 14.1 days.. Pulmonary toxicity due to sirolimus should be included in the differential diagnosis of kidney transplant patients who display signs of interstitial pneumonia. Its diagnosis is difficult requiring exclusion of other pulmonary diseases. Resolution of the symptoms was quick after suspension of the drug.

Topics: Adult; Aged; Bacterial Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung; Middle Aged; Sirolimus; Tomography, X-Ray Computed

Several of the new immunosuppressive agents that are used to treat transplant recipients possess in vitro activity against specific pathogens, enhance the activity of antimicrobial agents, or have unique drug interactions with antimicrobial agents. Mycophenolate mofetil may have a protective effect against Pneumocystis carinii; it also enhances the activity of ganciclovir and has strong antiviral activity against human immunodeficiency virus type 1. High doses of mycophenolate mofetil have been associated with a higher frequency of tissue-invasive cytomegalovirus disease but not with asymptomatic cytomegalovirus infection. Rapamycin exhibits potent in vitro fungicidal activity against Cryptococcus neoformans and several pathogenic fungi in transplant recipients; however, it is not known whether its immunosuppressive effect in organ transplant recipients outweighs its antifungal activity. Recognition of the unique characteristics of these agents and the evolving spectrum of opportunistic infections has implications for the differential diagnosis, management, and prophylaxis of infections in organ transplant recipients in the modern immunosuppressive era.

Topics: Anti-Infective Agents; Antibodies, Monoclonal; Bacterial Infections; Clinical Trials as Topic; Drug Interactions; Humans; Immunosuppressive Agents; Opportunistic Infections; Organ Transplantation; Sirolimus