One major class of antibiotics inhibits the synthesis of ..
Inhibition of lipid synthesis in Escherichia coli cells by the antibiotic cerulenin
ANTIBIOTICS: INHIBITION OF PROTEIN SYNTHESIS
C55-P serves as the central carrier in several processes concerned with membrane trafficking of mono-, di-, and oligosaccharides which constitute the building blocks of bacterial cell walls and capsules. Therefore, it is very likely that friulimicin blocks multiple pathways, as illustrated in the proposed model (Fig. ). It will be interesting to see whether targeting of C55-P by friulimicin will further lead to a multiplicity of cellular events comprising sequestration of the lipid carrier from the septum area and aberrant cell septation, as observed with some lantibiotics ().
As demonstrated by TLC (Fig. ), recombinant purified MraY-His6 was able to synthesize lipid I from its substrates C55-P and UDP-MurNAc-pp (lane 2). Complete conversion of the lipid carrier was not attainable because of the reversibility of the reaction (). Like the specific MraY inhibitor tunicamycin, friulimicin almost completely inhibited the formation of lipid I.
Antimetabolites: Antibiotics That Inhibit Nucleotide Synthesis
While our results clearly demonstrate that, in spite of sharing some structural features, friulimicin and daptomycin differ in the molecular mode of antibiotic action, they unfortunately do not provide any hints as to a molecular target for daptomycin in the cell wall biosynthesis pathway, particularly in the membrane-associated steps. Such activities had been suggested in early work on daptomycin (, , ) and by transcriptional profile analysis of daptomycin-treated S. aureus cells (). In addition, comparative transcriptomic and proteomic analysis of friulimicin versus daptomycin with B. subtilis supported such a view (), although this study also identified differences in the response patterns which point toward distinctions between their antibiotic activities on the molecular level.
Though I have seen no medical reports of iodine therapy for kidney stones, the high amount of iodide excretion in urine suggests that it should be worth a try in some cases, particularly those with small stones and signs of infection, ie. white blood cells and bacteria in the urine. Since iodine is not as actively secreted in the bile, it would not seem as profitable. But wait, the Mayo Clinic group reported that iodide showed up not only in kidney and bladder but also in liver and spleen, though in lesser amount. In addition, it is well known that iodide does bind to cholesterol and to unsaturated fatty acids, which are found in bile. There is no reason to doubt that iodine reacts these organs and that it might reach antibiotic concentrations and be sufficiently active to dissolve cholesterol and lipid materials that complicate stones. This deserves formal research study.
Bacitracin inhibits lipid phosphatase, ..
The lantibiotic mersacidin inhibits peptidoglycan biosynthesis at the level of transglycosylation (). The results presented here demonstrate that the molecular basis of this inhibition is the tight interaction with the membrane-bound peptidoglycan precursor, undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-GlcNAc (lipid II). (i) The numbers of binding sites determined by adsorption of [14C]mersacidin are in agreement with a specific interaction of an antibiotic with a lipid intermediate in the peptidoglycan biosynthetic cycle. (ii) The binding capacities of M. luteus and S. simulans were influenced by the energy state of the cells, and the numbers of target sites were considerably reduced by de-energization with the protonophore CCCP or by starvation in buffer. (iii) The adsorption of [14C]mersacidin to growing cells (Table ), as well as to isolated membranes (Fig. ), was strictly dependent on the availability of lipid II, and inhibitors of lipid II synthesis interfered with binding. (iv) Mersacidin strongly bound to purified micelles of lipid II during gel electrophoresis (Fig. ), and lipid II completely antagonized the bacteriocidal activity of the lantibiotic (Table ).
The interaction of mersacidin with lipid II seems to involve substantial portions of both molecules. Even when employed at high concentrations, none of the individual building blocks of the lipid II molecule (Fig. ) or structurally related compounds were able to antagonize the activity of the lantibiotic (Table ). This provides some information on the molecular nature of the target site. Several lines of evidence indicate that mersacidin does not interact with the C-terminal -alanyl–-alanine portion of the lipid intermediate. (i) The lantibiotic is not antagonized by any of the acyl--Ala–-Ala-containing structures listed in Table , including UDP-MurNAc-pentapeptide which contains the entire pentapeptide side chain. Therefore, its molecular mechanism of action differs from that of the glycopeptide antibiotic vancomycin, for which complex formation with this portion of the peptidoglycan precursors has been established (; for reviews, see references and ). (ii) The binding of mersacidin to growing cells (Table ), as well as to isolated membranes (Fig. ), was not inhibited by vancomycin, indicating simultaneous adsorption and thus different binding sites for the two antibiotics. (iii) It has been shown previously that mersacidin is active against vancomycin-resistant Enterococcus faecium, which synthesizes an alternative peptidoglycan precursor terminating in -alanyl–-lactate, for which vancomycin has a low affinity, and that it inhibits in vitro peptidoglycan synthesis from UDP-MurNAc-tripeptide, a precursor which lacks the two C-terminal amino acid residues (). Consequently, the peptide side chain of the lipid intermediate is unlikely to be involved in complex formation, leaving the disaccharide moiety, the pyrophosphate group, and the undecaprenyl residue as possible candidates for an interaction (Fig. ). An involvement of the disaccharide headgroup is supported by the finding that even high concentrations of mersacidin did not interfere with the translocase II reaction (); thus, mersacidin seems to have a significantly higher affinity for lipid II than for lipid I, which lacks the GlcNAc residue. On the other hand, the interaction of mersacidin with lipid II appears to involve more than just the disaccharide unit, as its affinity for lysozyme-digested cell walls of M. luteus, in which free disaccharide headgroups are available, as well as for GlcNAc-MurNAc-Ala–-iso-Gln was too low to antagonize its growth-inhibitory activity (Table ). Barrett et al. () observed an increased bactericidal activity of mersacidin in a calcium-enriched medium, which may hint at an involvement of the pyrophosphate moiety of the lipid intermediate. With respect to the possible ratio of mersacidin and lipid II in complex formation, it is noteworthy that lipid II micelles adsorbed approximately equimolar amounts of mersacidin (Fig. ).
Start studying Antibiotics: Inhibit Growth of Bacteria (1)
Rethinking Ramoplanin: The Role of Substrate Binding …
Inhibition of lipid-linked saccharide synthesis: Comparison of tunicamycin, streptovirudin, and antibiotic 24010
Bacteria: Metabolism-Antibiotic Sensitivity
19/12/2017 · Inhibition of protein synthesis also inhibits synthesis of lipid-linked ..
THE BACTERIA Metabolism-Antibiotic ..
28/04/2016 · The Lantibiotic Mersacidin Inhibits Peptidoglycan Synthesis by Targeting Lipid II.
is transferred from UDP to a carrier lipid and is then modified to ..
De-energized cells had a strongly reduced binding capacity for [14C]mersacidin. When M. luteus ATCC 4698 was starved in buffer for 2 h prior to the addition of the label, the amount of mersacidin bound was up to 30 times lower than that adsorbed by an exponentially growing culture. Similarly, treatment of S. simulans 22 for 30 min with the protonophore CCCP reduced the amount of [14C]mersacidin adsorbed to 14% of that of an untreated control culture. It is conceivable that during de-energization the available lipid II molecules are converted into polymeric peptidoglycan, while their energy-requiring de novo synthesis is prevented under these circumstances. Therefore, we tried to trap lipid II in the monomeric state by vancomycin before de-energizing the cells. To this end, we incubated an additional culture aliquot of S. simulans with vancomycin for 5 min prior to the addition of CCCP, which increased the binding capacity of de-energized cells from 14 to 84%.
Daptomycin inhibits cell envelope synthesis by …
Of all inhibitors of transglycosylation that were employed in this study, only the structurally related lantibiotic actagardine interfered with the adsorption of mersacidin (Table ; Fig. ). The concentrations of actagardine necessary for inhibition of transglycosylation in vitro paralleled those of mersacidin and vancomycin but were 2 to 3 orders of magnitude higher than that of the competitive enzyme inhibitor moenomycin (, , ). This result suggests an interaction of actagardine with lipid II rather than with the transglycosylase and, together with the observations that it prevented the binding of mersacidin and that its activity was not antagonized by bisacetyl-Lys–-Ala–-Ala (Table ), indicates that actagardine competes with mersacidin for the same target binding site. The two lantibiotics contain one ring structure that has been almost completely conserved in both molecules (, , ). It is tempting to suggest that this conserved sequence motif is the structural basis for their activity. Both peptides interact with a novel target site on the lipid II molecule and may therefore be the prototypes for a new class of chemotherapeutic agents. In this context it is noteworthy that both lantibiotics are also active against the pseudomurein-containing Methanobacterium archaebacteria (, ), suggesting that they bind to a highly conserved portion of the lipid intermediate. The promising in vivo activities of mersacidin against methicillin-resistant Staphylococcus aureus () and of actagardine against Streptococcus pneumoniae () indicate the potential of these lantibiotics for future development of drugs against these problematic pathogens, particularly since altered peptides can be constructed by manipulation of their structural genes ().
08/11/2016 · National Academy of Sciences
The finding that Lys inhibits a distinct step in the PG synthesis pathway from the A and E proteins indicates that small phages, particularly the single-stranded RNA (ssRNA) leviviruses, have a previously unappreciated capacity for evolving novel inhibitors of PG biogenesis despite their limited coding potential.
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