Bacteria
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
Components in cell envelopes are important in host-parasite interactions. LPS is an important virulence factor. For example, Neisseria meningitidis, a Gram-negative bacterium, causes the diseases meningitis and bacteremia in humans; sometimes accompanied by septic shock, a process that is induced by LPS from the organism. Many of the proteins and polysaccharides in cell walls are antigenic or act as haptens in immunological reactions. Detection of these antigens often aids in the diagnosis of infections. For example, detection of LPS indicates infection with a Gram-negative bacterium. The lipid A is the part of LPS that is primarily responsible for the endotoxemia that is associated with many Gram-negative bacterial infections. Antibiotic treatment often results in liberation of LPS from the bacteria following their lysis. As a result, clinical endotoxemia symptoms may develop after treatment with antibiotics, also, many commercial foods, bottled water, as well as sterile water used for intravenous applications are routinely analyzed for LPS to assure the absence of these virulence factors.
Immune Modulation In Sepsis
Thomas F. Kresina in Immune Modulating Agents, 2020
The clinical syndrome of sepsis encompasses infection but is an ill-defined and heterogeneous concept that seems to extend beyond infection to include a variety of different causes with differing prognoses. Similar clinical manifestations occur regardless of whether the primary insult is invasive infection, massive trauma, or extensive tissue necrosis. Until the mid-1980s gram-negative infection, mediated through endotoxin, was considered to cause the most lethal form of sepsis. The classical features of a warm, vasodilated, and hypotensive patient with a high cardiac output spiraling into irreversible multiple organ failure were thought to be entirely due to endotoxin. Endotoxin was recognized to be a component of the bacterial cell wall, and the lipid A component was a virulence factor common to all gram-negative organisms. As lipid A is common to all gram-negative organisms, it was thought to be an ideal target for modulating the response to severe sepsis and improving outcome, and the first attempts at nonantibiotic therapy were therefore aimed at counteracting the effect of endotoxin.
Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date *
Valerio Voliani in Nanomaterials and Neoplasms, 2021
In terms of intravenous delivery, classical liposomes typically exhibit short circulating half-lives due to rapid clearance. In general, the lipid bilayer structure of liposomes results in recognition by the immune system and subsequent clearance from circulation by macrophages. Clearance has been minimized by PEGylation of the liposome surface. PEGylated liposomal doxorubicin (Doxil®), the first example of a liposomal nanoparticle drug, was proven effective in the reduction of cardiotoxic side effects of doxorubicin treatment. Doxil® has been approved for Karposi’s sarcoma, ovarian cancer, and multiple myeloma, as well as for metastatic breast cancer [51]. In comparison to free doxorubicin (DOX), the PEGylated liposome resulted in 4 to 16 fold enhancement of drug levels in malignancies [52]. The PEGylated liposomal carrier was quickly adopted for the delivery of other drugs such as Ambisome®, an amphotericin B to treat fungal infections, and Visudyne®, delivering verteporphin for wet macular degeneration [53, 54]. These and many of the other approved liposomes rely strictly on passive targeting which successfully increases distribution to diseased tissue.
Can octapeptin antibiotics combat extensively drug-resistant (XDR) bacteria?
Published in Expert Review of Anti-infective Therapy, 2018
Mark A. T. Blaskovich, Miranda E. Pitt, Alysha G. Elliott, Matthew A. Cooper
The polymyxins act primarily via disruption of the integrity of the outer membrane of Gram-negative bacteria. It is well established that this proceeds by initially binding to lipid A, the basal component of lipopolysaccharide (LPS) that is anchored on the outer membrane of Gram-negative bacteria and essential for bacterial viability (see Figure 4). Numerous biophysical techniques (ITC, NMR, SPR) have been used to characterize the interaction of Pmx with bacterial membranes [91]. The multiple positive charges from the Dabside chains on the polar face of the amphipathic polymyxin interact with the anionic polar phosphate head group of lipid A, displacing Mg2+ and Ca2+ divalent cations that bridge the lipid A phosphoesters. This displacement destabilizes the outer membrane and facilitates insertion of the lipophilic face of polymyxin into the membrane, resulting in disruption of the packing of the hydrophobic acyl chains of lipid A. Polymyxin then inserts into the inner membrane, leading to cell lysis and death. Additional mechanisms have been postulated above and beyond the membrane disruption, such as binding to ribosomal RNA [92] and inhibition of NADH-quinone oxidoreductase activity [57], but it is not clear how significant these other properties are at contributing to the overall killing activity.
Investigation of dimyristoyl phosphatidyl glycerol and cholesterol based nanocochleates as a potential oral delivery carrier for methotrexate
Published in Journal of Liposome Research, 2022
Bothiraja Chellampillai, Sneha Kashid, Atmaram Pawar, Ashwin Mali
The DMPG-Na was selected for the formulation of nanoliposomes. The various types of nanocochleates such as rolled, cylindrical, spherical and planar have been reported by using several acidic phospholipids (Zarif 2005). The anionic saturated phospholipid with two 14C atoms chains was widely reported for the preparation of nanocochleates. This lipid represents the major component of membranes of gram-positive bacteria (Umeyama et al. 2006). Further, cholesterol has the ability to form complexes with drugs as well as to stabilise the phospholipid membranes, followed by encapsulation of MTX (Poudel et al. 2018). The NLs were prepared to have an increasing amount of MTX (3, 5 and 7mg) to achieve maximum loading of MTX into the lipid bilayers and were evaluated for particle size and encapsulation efficiency. The NLs size was increased in proportion to MTX concentration which was ranging from 3mg (MTX-NL1) to 5mg (MTX-NL2) as depicted in Table 1. But, the gradual increase in terms of 7mg (MTX-NL3) resulted in low encapsulation efficiency.
TLR4 as a therapeutic target for respiratory and neurological complications of SARS-CoV-2
Published in Expert Opinion on Therapeutic Targets, 2021
Dhriti Kaushik, Ranjana Bhandari, Anurag Kuhad
Thus, modulating TLR4 signaling provides a promising route that can be taken to combat the hyperinflammatory reaction. Modulating the TLR4 signaling could be by both ways, by using agonists and antagonists. Lipid A, a lipid component of endotoxin has an acyl-chain region that is recognized by TLR4 and CD14 in most of the cells. This triggers the innate immune signaling pathway and leads to the translocation of NF-κB and the release of pro-inflammatory cytokines and inflammatory mediators. There could be some potency differences in Lipid A depending upon the microbial species, the humidity and temperature, and the interaction with the immune system of the host [84]. The backbone of Lipid A is formed by 1,4-diphosphorylated glucosamine to which fatty acid acyl chains of variables lengths can be attached. The development of novel TLR4 agonists is based on the development of simpler structures than Lipid A. Lipid A has a biosynthetic precursor Lipid X that shows antagonistic activity for TLR4 is the simpler monosaccharide that can be used as the basis for TLR4 antagonists, like FP7-like compounds [85–87].
Related Knowledge Centers
- Acyl Group
- Amino Sugar
- Bacterial Outer Membrane
- Fatty Acid
- Glucosamine
- Lipopolysaccharide
- Phosphate
- Toxicity
- Lipid
- Gram-Negative Bacteria