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At least 289 records · Page 16Linked to original sources
PubMed1998

Controlling antimicrobial resistance: a proposed transferable permit market.

Resistance to antimicrobials results in those antimicrobials becoming ineffective in treating common bacterial infections. To prevent the spread of such resistance the use of antimicrobials requires control. The authors have previously argued that use of regulation or charges to control resistance would not be efficient. Regulation will not account for different marginal costs of reducing antimicrobial prescription amongst GPs, and charges, although based on sound economic concepts, are based on an unrealistic amount of required information. It was therefore argued that a system of tradable permits, by combining the targets of regulation and the market flexibility of charges, would achieve control more efficiently than simple regulation or charges. In this paper the authors progress this proposed policy by considering various important issues which arise when designing such a tradable permit system for antimicrobials. The paper does not provide an exhaustive plan enabling a blueprint for such a market to be designed, but a proposal which may be used as platform for further specific development of such an initiative to deal with resistance.

Anti-Bacterial Agents↗
PubMed1994

Identification of the DNA-binding site for the phosphorylated VanR protein required for vancomycin resistance in Enterococcus faecium.

The vancomycin resistance operon of Enterococcus faecium encodes a two-component regulatory system comprising VanS and VanR. In vitro experiments showed that about 5% of a labile phosphorylated VanR (P-VanR) was accumulated from ATP and a maltose-binding protein-VanS fusion protein (MBP-VanS). Alternatively, about an 8% abundance of P-VanR was produced with acetyl phosphate. In such incubations, gel shift experiments revealed that P-VanR selectively bound to a 254-bp DNA fragment that contains the vanH promoter for the vanH, vanA, and vanX structural genes. When VanS was added with a mole ratio for VanS:VanR of higher than 1:1, VanS competed with DNA for P-VanR and abolished the gel shift. P-VanR bound 500-fold more tightly to the vanH promoter region, with an estimated EC50 of 40 nM, than the unphosphorylated VanR. A second DNA fragment of 197 bp containing the proposed vanR promoter for the vanR and vanS regulatory genes also exhibited gel shift, but with much lower affinities. A mutant VanR(D53A) was shown to be incompetent for phosphorylation by phosphorylated MBP-VanS or by acetyl phosphate; however, it still bound DNA specifically, albeit with low affinity. DNase I footprinting by P-VanR revealed that a ca. 80-bp region was protected on the vanH promoter and a ca. 40-bp region was protected on the vanR promoter. The unphosphorylated VanR footprinted the same 80 bp on the vanH promoter, but only 20 bp on the vanR promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed2002

Stereospecificity of aminoglycoside-ribosomal interactions.

Aminoglycoside antibiotics bind to the A-site decoding region of bacterial rRNA causing mistranslation and/or premature message termination. Aminoglycoside binding to A-site RNA decoding region constructs is established here to be only weakly stereospecific. Mirror-image prokaryotic A-site decoding region constructs were prepared in the natural D-series and the enantiomeric L-series and tested for binding to a series of aminoglycosides. In general, aminoglycosides bind to the D-series decoding region constructs with 2-3-fold higher affinities than they bind to the enantiomeric L-series. Moreover, L-neamine, the enantiomer of naturally occurring D-neamine, was prepared and shown to bind approximately 2-fold more weakly than D-neamine to the natural series decoding region construct, a result consistent with weakly stereospecific binding. The binding of naturally occurring D-neamine and its synthetic L-enantiomer was further evaluated with respect to binding to prokaryotic and eukaryotic ribosomes. Here, weak stereospecifcity was again observed with L-neamine being the more potent binder by a factor of approximately 2. However, on a functional level, unnatural L-neamine proved to inhibit in vitro translation with significantly lower potency (approximately 5-fold) than D-neamine. In addition, both L- and D-neamine are bacteriocidal toward Gram-(-) bacteria. L-Neamine inhibits the growth of E. coli and P. aeruginosa with 8- and 3-fold higher MIC than D-neamine. Interestingly, L-neamine also inhibits the growth of aminoglycoside-resistant E. coli, which expresses a kinase able to phosphorylate and detoxify aminoglycosides of the D-series. These observations suggest that mirror-image aminoglycosides may avoid certain forms of enzyme-mediated resistance.

Anti-Bacterial Agents↗
PubMed1998

Inhibition of in vitro and in vivo HIV replication by a distamycin analogue that interferes with chemokine receptor function: a candidate for chemotherapeutic and microbicidal application.

Select chemokine receptors act as coreceptors for HIV-1 entry into human cells and represent targets for antiviral therapy. In this report we describe a distamycin analogue, 2,2'-[4, 4'-[[aminocarbonyl]amino]bis[N,4'-di[pryrrole-2-carboxamide- 1, 1'-dimethyl]]-6,8-naphthalenedisulfonic acid]hexasodium salt (NSC 651016), that selectively inhibited chemokine binding to CCR5, CCR3, CCR1, and CXCR4, but not to CXCR2 or CCR2b, and blocked chemokine-induced calcium flux. Inhibition was not due to nonspecific charge interactions at the cell surface, but was based on a specific competition for the ligand receptor interaction sites since the inhibitory effect was specific for some but not all chemoattractant receptors. NSC 651016 inhibited in vitro replication of a wide range of HIV-1 isolates, as well as HIV-2 and SIV, and exhibited in vivo anti-HIV-1 activity in a murine model. In contrast, a distamycin analogue with similar structure and charge and the monomeric form of NSC 651016 demonstrated no inhibitory effects. These data demonstrate that molecules which interfere with HIV-1 entry into cells by targeting specific chemokine coreceptors can provide a viable approach to anti-HIV-1 therapy. NSC 651016 represents an attractive candidate for the chemotherapeutic treatment of HIV-1 infection and as a microbicide to prevent the sexual transmisssion of HIV-1. Moreover, NSC 651016 can serve as a template for medicinal chemical modifications leading to more effective antivirals.

Administration, Cutaneous↗
PubMed2000

In vivo selection of functional ribosomes with variations in the rRNA-binding site of Escherichia coli ribosomal protein S8: evolutionary implications.

The highly conserved nature of rRNA sequences throughout evolution allows these molecules to be used to build philogenic trees of different species. It is unknown whether the stability of specific interactions and structural features of rRNA reflects an optimal adaptation to a functional task or an evolutionary trap. In the work reported here, we have applied an in vivo selection strategy to demonstrate that unnatural sequences do work as a functional replacement of the highly conserved binding site of ribosomal protein S8. However, growth competition experiments performed between Escherichia coli isolates containing natural and unnatural S8-binding sites showed that the fate of each isolate depended on the growth condition. In exponentially growing cells, one unnatural variant was found to be equivalent to wild type in competition experiments performed in rich media. In culture conditions leading to slow growth, however, cells containing the wild-type sequence were the ultimate winner of the competition, emphasizing that the wild-type sequence is, in fact, the most fit solution for the S8-binding site.

Base Sequence↗
PubMed1999

Initial binding sites of antimicrobial peptides in Staphylococcus aureus and Escherichia coli.

We examined the initial binding sites of magainin 1, cecropin P1 and lactoferricin B in Staphylococcus aureus and Escherichia coli. All 3 peptides were active against E. coli, whereas only lactoferricin B exerted any activity against S. aureus. Soluble lipoteichoic acid and lipopolysaccharide both interacted with all 3 peptides, whereas soluble teichoic acid interacted with lactoferricin B only. Antibodies against teichoic acid diminished the activity of lactoferricin B, while antibodies against lipoteichoic acid had no influence on the activity of lactoferricin B. Antibodies against lipopolysaccharide diminished the activity of lactoferricin B and magainin 1, but had no effect on the activity of cecropin P1 against E. coli. We conclude that the initial binding sites of lactoferricin B in S. aureus, and of lactoferricin B and magainin 1 in E. coli, are teichoic acid and lipopolysaccharide, respectively. Cecropin P1 seems to interact with a different binding site than those of magainin 1 and lactoferricin B in E. coli.

Anti-Bacterial Agents↗
PubMed1994

Overexpression of the thiostrepton-resistance gene from Streptomyces azureus in Escherichia coli and characterization of recognition sites of the 23S rRNA A1067 2'-methyltransferase in the guanosine triphosphatase center of 23S ribosomal RNA.

The thiostrepton-resistance gene encoding the 23S rRNA A1067 methyltransferase from Streptomyces azureus has been overexpressed in Escherichia coli using a T7-RNA-polymerase-dependent expression vector. The protein was efficiently expressed at levels up to 20% of total soluble protein and purified to near homogeneity. Kinetic parameters for S-adenosyl-L-methionine (Km = 0.1 mM) and an RNA fragment containing nucleotides 1029-1122 of the 23S ribosomal RNA from E. coli (Km = 0.001 mM) were determined. S-Adenosyl-L-homocysteine showed competitive product inhibition (Ki = 0.013 mM). Binding of either thiostrepton or protein L11 inhibited methylation. RNA sequence variants of the RNA fragment with mutations in nucleotides 1051-1108 were tested as substrates for the methylase. The experimental data indicate that methylation is dependent on the secondary structure of the hairpin including nucleotide A1067 and the exact sequence U(1066)-A(1067)-G(1068)-A(1069)-A(1070) of the single strand.

Base Sequence↗
PubMed2006

Quantifying the roles of immigration and chance in shaping prokaryote community structure.

Naturally occurring populations of bacteria and archaea are vital to life on the earth and are of enormous practical significance in medicine, engineering and agriculture. However, the rules governing the formation of such communities are still poorly understood, and there is a need for a usable mathematical description of this process. Typically, microbial community structure is thought to be shaped mainly by deterministic factors such as competition and niche differentiation. Here we show, for a wide range of prokaryotic communities, that the relative abundance and frequency with which different taxa are observed in samples can be explained by a neutral community model (NCM). The NCM, which is a stochastic, birth-death immigration process, does not explicitly represent the deterministic factors and therefore cannot be a complete or literal description of community assembly. However, its success suggests that chance and immigration are important forces in shaping the patterns seen in prokaryotic communities.

Archaea↗
PubMed1984

Role of Bacteroides bivius beta-lactamase in beta-lactam susceptibility.

The susceptibility of 46 clinical isolates of Bacteroides bivius to amoxicillin, cefotaxime, cefoxitin, ceftizoxime, cephaloridine, cephalothin, moxalactam, penicillin G, amoxicillin plus clavulanic acid in a ratio of 2:1, carbenicillin, cefamandole, and ceftazidime was determined by an agar dilution technique. For the first eight agents susceptibility testing was also done with the addition of clavulanic acid (0.75 microgram/ml). For all agents, beta-lactamase-positive strains (35, using a nitrocefin slide test) were inhibited at higher concentrations than beta-lactamase-negative strains. Clavulanic acid reduced the susceptibility of the beta-lactamase-positive strains to the level of the beta-lactamase-negative strains to all agents. We prepared crude extracts of beta-lactamase from six strains. Activity against nitrocefin was directly related to their susceptibilities. The beta-lactamase had a mixed-substrate profile, hydrolyzing both penicillins and cephalosporins. Our results suggest a slow inactivation of cefoxitin, ceftizoxime, and moxalactam by the beta-lactamase. Clavulanic acid and cefoxitin inhibited the enzyme, whereas p-hydroxymercuribenzoate and cloxacillin did not. Thus, there was a clear relationship between beta-lactamase activity and susceptibility to beta-lactams, including cefoxitin and third-generation cephalosporins. The substrate and inhibition profiles of the B. bivius beta-lactamase were different from those of enzymes found in the "B. fragilis group."

Anti-Bacterial Agents↗
PubMed2001

Efficacies of lipophilic inhibitors of dihydrofolate reductase against parasitic protozoa.

Competitive inhibitors of dihydrofolate reductase (DHFR) are used in chemotherapy or prophylaxis of many microbial pathogens, including the eukaryotic parasites Plasmodium falciparum and Toxoplasma gondii. Unfortunately, point mutations in the DHFR gene can confer resistance to inhibitors specific to these pathogens. We have developed a rapid system for testing inhibitors of DHFRs from a variety of parasites. We replaced the DHFR gene from the budding yeast Saccharomyces cerevisiae with the DHFR-coding region from humans, P. falciparum, T. gondii, Pneumocystis carinii, and bovine or human-derived Cryptosporidium parvum. We studied 84 dicyclic and tricyclic 2,4-diaminopyrimidine derivatives in this heterologous system and identified those most effective against the DHFR enzymes from each of the pathogens. Among these compounds, six tetrahydroquinazolines were effective inhibitors of every strain tested, but they also inhibited the human DHFR and were not selective for the parasites. However, two quinazolines and four tetrahydroquinazolines were both potent and selective inhibitors of the P. falciparum DHFR. These compounds show promise for development as antimalarial drugs.

Alleles↗
PubMed1995

TmrB protein, which confers resistance to tunicamycin on Bacillus subtilis, binds tunicamycin.

Overproduction of TmrB protein, a 22.5-kDa protein with an N-terminal ATP-binding region and a C-terminal amphiphilic alpha-helix, confers resistance to tunicamycin on Bacillus subtilis. TmrB protein was found to bind Sepharose 6B to which tunicamycin was covalently linked. Experiments with mutant proteins found that the C-terminal region of TmrB protein might be involved in the binding to tunicamycin.

Bacillus subtilis↗
PubMed2003

Biopesticides.

The term 'biopesticide' encompasses a broad array of microbial pesticides, biochemicals derived from micro-organisms and other natural sources, and processes involving the genetic incorporation of DNA into agricultural commodities that confer protection against pest damage (plant-incorporated protectants). Some microbial pesticides, such as Bacillus thuringiensis, have a long history of safe and effective use as a biological insecticide. More recent developments in microbial pest control include the utilisation of other bacterial and fungal species that may competitively inhibit the growth of pathogenic and toxigenic micro-organisms on important agricultural commodities. The use of microbes and their gene products introduces additional considerations to the toxicological dose-response relationship, including a need to determine the plausibility of infectious and immunological effects in association with human exposure to these biopesticides in food or the environment. Studies of substantial equivalence suggest that foods currently derived from plant-incorporated protectants are not likely to differ from conventional foods. However, there is general consensus that the scientific methods to assess risks from genetically modified foods and micro-organisms will continue to evolve in the future.

Agriculture↗
PubMed1983

Configuration of the methoxyimino group and penetration ability of cefotaxime and its structural analogues.

Among the different mechanisms by which bacteria are resistant to beta-lactam antibiotics, three are of major interest: production of beta-lactamase, modifications of the target penicillin-binding proteins (PBPs) and decreased permeability. Cefotaxime (CTX) is a recently synthesized cephalosporin derivative, active against beta-lactamase producing Gram-negative bacteria and possessing in the acylamino side chain a methoxyimino group in the syn-configuration. It has been compared for affinity to PBPs and penetration ability with its isomer possessing the same group in the anti-configuration and the corresponding demethoxyimino derivative. The anti-isomer, although resistant to beta-lactamase, is devoid of antibacterial activity (MIC for Escherichia coli higher than 500 micrograms/ml). The affinities of CTX and its analogues for the PBPs of several strains of E. coli have been determined in vivo and in vitro by competition experiments using intact cells and bacterial envelopes, respectively. Only minor differences in the affinity for the target PBPs were detected in vitro. However, in vivo studies proved that the 50% saturating concentrations for the PBPs were more than 100-fold higher for the anti-isomer than for CTX. The reported results suggest that a very simple structural modification of the CTX molecule greatly decreases the penetration ability of the antibiotic through the outer cell layers, thus dramatically affecting its antibacterial properties.

Binding, Competitive↗
PubMed1987

A single mutation confers vanadate resistance to the plasma membrane H+-ATPase from the yeast Schizosaccharomyces pombe.

A single-gene nuclear mutant has been selected from the yeast Schizosaccharomyces pombe for growth resistance to Dio-9, a plasma membrane H+-ATPase inhibitor. From this mutant, called pma1, an ATPase activity has been purified. It contains a Mr = 100,000 major polypeptide which is phosphorylated by [gamma-32P] ATP. Proton pumping is not impaired since the isolated mutant ATPase is able, in reconstituted proteoliposomes, to quench the fluorescence of the delta pH probe 9-amino-6-chloro-2-methoxy acridine. The isolated mutant ATPase is sensitive to Dio-9 as well as to seven other plasma membrane H+-ATPase inhibitors. The mutant H+-ATPase activity tested in vitro is, however, insensitive to vanadate. Its Km for MgATP is modified and its ATPase specific activity is decreased. The pma1 mutation decreases the rate of extracellular acidification induced by glucose when cells are incubated at pH 4.5 under nongrowing conditions. During growth, the intracellular mutant pH is more acid than the wild type one. The derepression by ammonia starvation of methionine transport is decreased in the mutant. The growth rate of pma1 mutants is reduced in minimal medium compared to rich medium, especially when combined to an auxotrophic mutation. It is concluded that the H+-ATPase activity from yeast plasma membranes controls the intracellular pH as well as the derepression of amino acid, purine, and pyrimidine uptakes. The pma1 mutation modifies several transport properties of the cells including those responsible for the uptake of Dio-9 and other inhibitors (Ulaszewski, S., Coddington, A., and Goffeau, A. (1986) Curr. Genet. 10, 359-364).

Adenosine Triphosphate↗
PubMed1999

Evolution of microbial diversity during prolonged starvation.

Models of evolutionary processes postulate that new alleles appear in populations through random spontaneous mutation. Alleles that confer a competitive advantage in particular environments are selected and populations can be taken over by individuals expressing these advantageous mutations. We have studied the evolutionary process by using Escherichia coli cultures incubated for prolonged periods of time in stationary phase. The populations of surviving cells were shown to be highly dynamic, even after many months of incubation. Evolution proceeded along different paths even when the initial conditions were identical. As cultures aged, the takeovers by fitter mutants were incomplete, resulting in the coexistence of multiple mutant forms and increased microbial diversity. Thus, the study of bacterial populations in stationary phase provides a model system for understanding the evolution of diversity in natural populations.

Biological Evolution↗
PubMed2006

Use of competitive DNA hybridization to identify differences in the genomes of bacteria.

Although recent technological advances in DNA sequencing and computational biology now allow scientists to compare entire microbial genomes, comparisons of closely related bacterial species and individual isolates by whole-genome sequencing approaches remains prohibitively expensive for most laboratories. Here we report the development and testing of a biochemical approach for targeted sequencing of only those chromosomal regions that differ between two DNA preparations. The method, designated GFE (genome fragment enrichment) uses competitive solution hybridization and positive selection to obtain genomic DNA fragments that are present in one pool of fragments but not another. Repeated comparisons of the genomes of Enterococcus faecalis and E. faecium led to the identification of 225 putative genome-specific DNA fragments. Species and strain variations within these fragments were confirmed by both experimental and bioinformatic analyses. The E. faecalis genome-specific sequences identified included both a preponderance of those predicted to encode surface-exposed proteins, as well as several previously described unique marker regions embedded within highly conserved rrn operons. The GFE strategy we describe efficiently identified genomic differences between two enterococcal genomes, and will be widely applicable for studying genetic variation among closely related bacterial species.

DNA, Bacterial↗
PubMed2001

DNA as a nutrient: novel role for bacterial competence gene homologs.

The uptake and stable maintenance of extracellular DNA, genetic transformation, is universally recognized as a major force in microbial evolution. We show here that extracellular DNA, both homospecific and heterospecific, can also serve as the sole source of carbon and energy supporting microbial growth. Mutants unable to consume DNA suffer a significant loss of fitness during stationary-phase competition. In Escherichia coli, the use of DNA as a nutrient depends on homologs of proteins involved in natural genetic competence and transformation in Haemophilus influenzae and Neisseria gonorrhoeae. Homologs of these E. coli genes are present in many members of the gamma subclass of Proteobacteria, suggesting that the mechanisms for consumption of DNA may have been widely conserved during evolution.

Colony Count, Microbial↗