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Native And Acquired Resistance To Infection With Cryptococcus Neoformans
Published in Hans H. Gadebusch, Phagocytes and Cellular Immunity, 2020
Cationic proteins from mammalian cell nuclei, polymorphonuclear leukocytes, and other cell lysosomes, from platelets as well as whole cells, have been prepared/tested for anticryptococcal activity in vitro.42,82 Most of the proteins exhibited some fungistatic activity, and many were fungicidal in microgram quantities. When slide preparations of treated cryptococci were examined,42 LCP-treated cells showed little morphological alteration when compared with untreated control cells. On the other hand, lysozyme, the histones, and β-lysin had induced a variety of effects that seemed to be specific for each protein. Arginine-rich histones, in contrast to lysine-rich preparations, agglutinated the cryptococcal cells. Lysine-rich histones uniformly induced intracellular changes in the form of apparent granular inclusions within cryptococci. Lysozyme was shown to affect the budding process resulting in cells that suggested (1) osmotic instability, (2) interference with synthesis of capsular polysaccharide, and (3) inability of reproductive units to separate. Vacuolation was the dominant feature in β-lysin-treated cells.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Normal levels of bilirubin in the serum are between 0.2 and 0.8 mg/dl. The bilirubin level is determined by the relative rate at which bile pigments enter or leave the circulation. Bilirubin is tightly bound to albumin, 2 mol of pigment to each protein molecule, corresponding to the normal amount of unconjugated bilirubin in the serum of adults.429,591 Minor amounts are found in globulin fractions. The excess bilirubin is rapidly metabolized, first to yellow oxidation products which are still partly associated with albumin, then further to colorless derivatives which bind preferably to globulins. The bilirubin phenolic hydroxyl groups and the protein amino groups play a part in the bond between the pigment and albumin. Probably, lysine residues provide the free amino groups. If these lysin residues are blocked by reactions with methylisourea, the binding capacity of the albumin is considerably reduced. Other properties of the albumin molecule are also important since other proteins with high lysine content, for example, γ-globulin, show no affinity to bilirubin. Bilirubin diglucuronide is also bound to serum albumin. There are four absorption sites for the conjugate per albumin molecule. Similarly to free bilirubin, an interaction between hydroxyl and amino groups takes place in the binding of bilirubin diglucuronate.68,227
Epilogue
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Attempts to use lytic phages as a treatment to suppress bacterial infections have long history. However, this approach was rapidly overlooked by the emergence of antibiotics. In the twenty-first century, when antibiotic resistance in pathogenic bacteria has become a growing problem in medicine, interest in the putative phage therapy applications was renewed. Although the RNA phage lysins were proclaimed in due time as novel phage antibiotics, as described in the Protein antibiotics section of Chapter 14, direct use of the RNA phages as phage therapy tools might raise many serious questions because of their narrow host list, limited lytic capacities, and rapid emergence of resistant bacteria.
Phage therapy in pediatrics: the way forward for difficult-to-treat infections?
Published in Expert Review of Anti-infective Therapy, 2022
Annaleise R. Howard-Jones, Jonathan R. Iredell, Ameneh Khatami
As an extension, phage lysins are seeing increased usage in the management of a wide range of infections from eliminating Staphylococcus aureus carriage for effective management of atopic dermatitis [18], a common and often debilitating condition carrying high morbidity for the child and family, to treatment of invasive bacterial pneumonia [19]. Such lysins, which carry the same benefits as phages themselves in terms of low toxicity and high target specificity, are also customizable so can be tailored to a pathogen of interest [19]. Phage therapy, including phage lysins, could thus be used as an alternative to antibiotics or as adjunctive therapy to ensure timely and effective cure of both common and difficult-to-treat infections, with fewer short- and long-term negative impacts, representing an untapped opportunity to optimize management of difficult infections in children.
Biological challenges of phage therapy and proposed solutions: a literature review
Published in Expert Review of Anti-infective Therapy, 2019
Katherine M Caflisch, Gina A Suh, Robin Patel
Pharmacodynamic and pharmacokinetic considerations alike expand in their complexity when phages or lysins are used in combination with other phages or lysins, or other antimicrobial agents. For each, the mechanism of action and removal from the body should be carefully defined prior to determining the dosing regimen in an effort to maximize antibacterial activity. Some combinations have shown synergy, while others exhibit additive benefit, and some display antagonism. The order of delivery may impact the therapeutic outcome. Kumaran et al. report an experiment in which planktonic and biofilm methicillin-resistant S. aureus was treated with phage SB-1 prior to or at the same time as rifampin, daptomycin, fosfomycin, ciprofloxacin, or vancomycin in vitro with sequential treatment outperforming simultaneous treatment. Similarly, treatment of S. aureus biofilms in vitro with phage SATA-8505 following vancomycin, dicloxacillin, cefazolin, tetracycline, or linezolid abrogated the antimicrobial effect [121].
Alternatives to antibiotics in an era of difficult-to-treat resistance: new insights
Published in Expert Review of Clinical Pharmacology, 2019
Jordi Rello, Francesca Romana Parisella, Antonio Perez
Sal200 is composed of a recombinant form of the phage endolysin SAL-1 (rSAL-1). Endolysins are a common area of research, their mechanism of action involves bacterial cell wall destruction and release of phage progeny. Preclinical trial of Sal200 in mice with a MRSA infection demonstrated a reduced bacterial count in the bloodstream and spleen, with even lower rates achieved when combined to antibiotics [28]. In a phase IIa clinical trial (NCT01855048) a total of 34 volunteers received Sal200, which demonstrated strong antibacterial activity and no serious adverse events were observed [29]. Another lysin, CF-301, is being tested in a phase 2 trial (NCT03163446) in hospitalized patients with MRSA bacteremia and endocarditis [30]. Other studies on lysins are being developed and are currently in preclinical stages [31–33].