In Payback: Debt and the Shadow Side of Wealth, Margaret Atwood examines different forms of debt and their various interrelations. Her work invites, but does not provide, an account or philosophy of ...debt or its deep implication in Christian beliefs such as sin, satisfaction, and atonement. This paper aims to bring to light insights into the link between debt and some aspects of Christian belief, especially the ideas of sin and satisfaction. It draws upon another unlikely source-the Ethics and political treatises of Spinoza. Spinoza’s view at least implies that the idea that sin (understood as the voluntary actions of a free agent) creates a ‘debt’ that is ‘paid’ by punishment is a potentially dangerous ‘fiction.’ Spinoza intuits that the subsumption of the idea of debt into notions of retribution, vengeance, satisfaction, or atonement, are driven by ‘superstition,’ envy, and hatred, and through imitating others’ hateful ideas of oneself. The idea of ‘debt’ is an artefact of civil authority that can only assume affective, normative purchase through internalizing fear of the implicit threat of punishment inherent in law. I will seek, finally, to suggest an implicit critique in Spinoza of the imaginative subsumption of debt into the space of religio.
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-
-desmethyl adduct. All the compounds were found to be potent inhibitors of both ...acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer's disease patient brains. Many of them displayed lower inhibitory concentrations of
AChE (IC
= 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and
BChE (IC
= 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against
AChE and was found to be even more active than donepezil and inhibited
AChE better than
AChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme.
An important cause of bacterial resistance to aminoglycoside antibiotics is the enzymatic acetylation of their amino groups by acetyltransferases, which abolishes their binding to and inhibition of ...the bacterial ribosome. Enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Mt) is one of such acetyltransferases, whose upregulation was recently established as a cause of resistance to aminoglycosides in clinical cases of drug-resistant tuberculosis. The mechanism of aminoglycoside acetylation by MtEis is not completely understood. A systematic analysis of steady-state kinetics of acetylation of kanamycin A and neomycin B by Eis as a function of concentrations of these aminoglycosides and the acetyl donor, acetyl coenzyme A, reveals that MtEis employs a random-sequential bisubstrate mechanism of acetylation and yields the values of the kinetic parameters of this mechanism. The implications of these mechanistic properties for the design of inhibitors of Eis and other aminoglycoside acetyltransferases are discussed.
Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium ...Escherichia coli Nissle 1917 (or "Nissle") exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin's affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae.
Future of Aminoglycosides: The End or Renaissance Houghton, Jacob L; Green, Keith D; Chen, Wenjing ...
Chembiochem : a European journal of chemical biology,
May 3, 2010, Letnik:
11, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Although aminoglycosides have been used as antibacterials for decades, their use has been hindered by their inherent toxicity and the resistance that has emerged to these compounds. It seems that ...such issues have relegated a formerly front-line class of antimicrobials to the proverbial back shelf. However, recent advances have demonstrated that novel aminoglycosides have a potential to overcome resistance as well as to be used to treat HIV-1 and even human genetic disorders, with abrogated toxicity. It is not the end for aminoglycosides, but rather, the challenges faced by researchers have led to ingenuity and a change in how we view this class of compounds, a renaissance.
Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such as linear alkyl chains on the ...AG backbone, interesting antibacterial and antifungal agents with a novel mechanism of action have been developed. Herein, we report the design and synthesis of seven kanamycin B (KANB) derivatives. Their antibacterial and antifungal activities, along with resistance/enzymatic, hemolytic, and cytotoxicity assays were also studied. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6″-position of KANB through a thioether linkage, exhibited good antibacterial and antifungal activity, were poorer substrates than KANB for several AG-modifying enzymes, and could delay the development of resistance in bacteria and fungi. Also, they were both relatively less hemolytic than the known membrane targeting antibiotic gramicidin and the known antifungal agent amphotericin B and were not toxic at their antifungal MIC values. Their oxidation to sulfones was also demonstrated to have no effect on their activities. Moreover, they both acted synergistically with posaconazole, an azole currently used in the treatment of human fungal infections.
Fosfomycin is a safe broad-spectrum antibiotic that has not achieved widespread use because of the emergence of fosfomycin-modifying enzymes.
Inhibition of fosfomycin-modifying enzymes could be used ...to help combat pathogens like Mycobacterium abscessus.
Our previous work identified several inhibitors for the enzyme FosB from Staphylococcus aureus.
We have tested those same compounds for inhibition of FosM, the fosfomycin-modifying enzyme from M. abscessus.
The work described here will be used as the basis for more detailed studies into the inhibition of FosM.
Aminoglycosides (AGs) are clinically relevant antibiotics used to treat infections caused by both Gram-negative and Gram-positive bacteria, as well as Mycobacteria. As with all current antibacterial ...agents, resistance to AGs is an increasing problem. The most common mechanism of resistance to AGs is the presence of AG-modifying enzymes (AMEs) in bacterial cells, with AG acetyltransferases (AACs) being the most prevalent. Recently, it was discovered that Zn(2+) metal ions displayed an inhibitory effect on the resistance enzyme AAC(6')-Ib in Acinetobacter baumannii and Escherichia coli. In this study, we explore a wide array of metal salts (Mg(2+), Cr(3+), Cr(6+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Au(3+) with different counter ions) and their inhibitory effect on a large repertoire of AACs AAC(2')-Ic, AAC(3)-Ia, AAC(3)-Ib, AAC(3)-IV, AAC(6')-Ib', AAC(6')-Ie, AAC(6')-IId, and Eis. In addition, we determine the MIC values for amikacin and tobramycin in combination with a zinc pyrithione complex in clinical isolates of various bacterial strains (two strains of A. baumannii, three of Enterobacter cloacae, and four of Klebsiella pneumoniae) and one representative of each species purchased from the American Type Culture Collection.
In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were ...established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs.
Vacuum assisted resin infusion molding (VARIM) was used to produce multiscale fiber reinforced composites (M-FRCs) based on carbon nanofibers dispersed in an epoxy resin. Flexural, interlaminar shear ...strength (ILSS) and thermomechanical tests are presented for the 0.1
wt% and 1
wt%
M-FRCs and compared with the neat fiber reinforced composites (FRCs). Flexural strength and modulus increased (16–20%) and (23–26%), respectively for the 0.1
wt% and 1
wt%
M-FRCs when compared to the neat FRCs. ILSS properties increased (6% and 25%) for the 0.1
wt% and 1
wt%
M-FRCs, respectively when compared to neat FRCs. The glass transition temperatures (
T
g) of both M-FRC samples were 25
°C higher than the neat FRC. Coefficients of thermal expansion (CTE) of the M-FRC samples improved compared to the neat FRC. The improved
T
g and CTE properties in the M-FRC samples are attributed to synergistic interactions between the CNF/PNC matrix and glass fibers.
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