The swift spread of infections caused by drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), has quickly become a worldwide concern as infections spread from healthcare settings to the wider community. While ferrocenyl chalcones, which are chalcone derivatives with antimicrobial activity, have gained attention from researchers, further study is needed to assess their cytotoxicity. Ten newly developed chalcones, in which ring A was replaced with a ferrocenyl moiety and ring B contained increasing alkyl chain lengths from 5-10 carbons, were assessed. Using 2-fold broth microdilution, the minimum inhibitory concentration (MIC) of five of the ten compounds were lower against Gram-positive organisms (MICs from 0.008 mg/ml to 0.063 mg/ml) than Gram-negative organisms (MICs = 0.125 mg/ml). These novel ferrocenyl chalcone compounds were effective against 3 types of clinically isolated drug-resistant S. aureus, including a MRSA, and against other non-resistant clinically isolated and laboratory-adapted Gram-positive bacteria. The same compounds inhibited growth in non-resistant bacteria by potentially obstructing cellular respiration in Gram-positive bacteria. Images obtained through scanning electron microscopy revealed fully lysed bacterial cells once exposed to a selected compound that showed activity. The results indicate that these newly developed compounds could be important antimicrobial agents in the treatment of infections from clinically resistant bacteria.
A conflict exists in the literature concerning the mode of translocation of D-glucose and D-ribose across the lysosome membrane. The more rapid net uptake of ribose, when measured by the osmotic-protection technique, has been attributed either to its smaller size and lower hydrogen-bonding capacity, or to a lower affinity for a transport system shared by both sugars. The latency of acid beta-hexosaminidase in isolated rat liver lysosomes was measured after preincubation for periods up to 1 h in various solutions containing glucose and/or ribose, and in some cases sucrose. After confirmation of the superior osmotic protection afforded by glucose (than by ribose), it was shown that a solution 0.125 M in both glucose and ribose provided protection intermediate between that given by 0.25 M-glucose and that given by 0.25 M-ribose. This result is inconsistent with the common-carrier hypothesis.
An osmotic-protection method has been used to study the permeability of rat liver lysosomes to 43 organic non-electrolytes of formula weights ranging from 62 to 1000. A lysosome-rich centrifugal fraction of rat liver homogenate was resuspended in an unbuffered 0.25 M solution of test solute, pH 7.0, and incubated at 25 degrees C for 60 min. The free and total activities of 4-methylumbelliferyl N-acetyl-beta-D-glucosaminidase were measured after incubation for 0, 30 and 60 min. Three patterns of results were seen. In pattern A the percentage free activity remained low throughout the 60 min incubation, indicating little or no solute entry into the lysosomes. In pattern B, the percentage free activity was initially low, but rose substantially during the incubation, indicating solute entry. In pattern C there was not even initial osmotic protection, indicating very rapid solute entry. The rapidity of solute entry into the lysosomes showed no correlation with the formula weight, but a perfect inverse correlation with the hydrogen-bonding capacity of the solutes. The results, which can be used to predict the ability of further compounds to cross the lysosome membrane by unassisted diffusion, are discussed in the context of metabolite and drug release from lysosomes in vivo.
Low concentrations of some neutral dipeptides, such as L-Ala-L-Ala, rapidly disrupt rat liver lysosomes. The phenomenon has been attributed to an osmotic imbalance generated by the production of amino acids in the lysosome by lysosomal dipeptidase activity. This hypothesis is challenged by testing several pairs of dipeptides available in both D- and L-forms and a range of dipeptides whose susceptibility to lysosomal dipeptidase activity is known. A good correlation was found between the lytic ability of dipeptides and their capacity to cross the lysosome membrane and be hydrolysed by lysosomal dipeptidase. The osmotic-imbalance hypothesis is critically evaluated in the light of the results and of recent information concerning the carrier-mediated transport of amino acids and dipeptides across the lysosome membrane. It is concluded that intralysosomal generation of amino acids remains the most plausible explanation of the lytic activity of dipeptides, and that the dipeptide porter(s) in the lysosome membrane must have higher Km than the amino acid porters.
Lysosomes are intracellular sites of macromolecule degradation confined by a membrane that localizes hydrolytic enzymes in close proximity to their macromolecular substrates. The monomeric products of digestion then cross the lysosome membrane and enter the cytosol to participate in further cellular metabolism. The mode of metabolite translocation was formerly considered to be diffusion, but latterly evidence has indicated the presence of carriers in the lysosome membrane (for reviews, see Reijngoud & Tager, 1977; Forster & Lloyd, 1988).In comparison with the transport of amino acids, for which kinetic studies have been performed on seven carriers to date, little is known about the mechanisms of sugar translocation across the lysosome membrane. Carriers for only two sugars, glucose and sialic acid, have so far been suggested. Evidence for the sialic acid porter comes mainly from the existence of Salla diseasc and sialic acid storage disease, in which dysfunction of the putative sialic acid carrier occurs (for example, see Renlund et ul., 1986). Studies on glucose (and ribose) transport across the lysosome membrane have been performed on modified lysosomes (Tritosomes), where glucose translocation was attributed to carrier-mediated transport ( K , 50 mM) and possibly free diffusion (Maguire et al., 1983). Sugars are known to cross other membranes by more than one mechanism: for example, erythritol enters erythrocytes by an approximately equal combination of transport and diffusion (W. D. Stein, personal communication).Our aim is to establish the diffusional component of glucose and ribose translocation across the lysosome membrane. The experimental approach chosen was to compare the uptake of these sugars with the uptake of a range of substances that, like the sugars, contain only carbon, hydrogen and oxygen. Most of the molecules studied are non-physiological and therefore unlikely to be substrates for transport systems; they were chosen to encompass a range of physicochemical parameters, particularly molecular size and hydrogen-bonding capacity.Relative net uptake rates were measured using the osmotic-protection method (Bird et al., 1 987), in which lyso-44 1 somes are suspended in 0.25 M solutions of the solute under investigation. Non-latent lysosomal hexosaminidase activity, assayed with a non-permeant substrate, indicates the proportion of broken lysosomes in the resuspension. A nonpermeant solute maintains lysosomal enzyme latency. Influx of the solute leads to osmotic imbalance and subsequent lysosome breakage. The osmotic-protection method does not require highly purified lysosome preparations and allows the study of solutes that are not available in radiolabelled form. However, the information gained on uptake rates is indirect and cannot fully establish the mechanism of uptake.The net uptake rates of the non-physiological compounds correlated well with their physico-chemical features. The data showed that an increase in hydrogen-bonding capacity is more important than an increase in molecular mass in ...
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