Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of alpha-helical cationic antimicrobial peptide variants with small amino acid changes was designed. Alterations in the charge, hydrophobicity, or length of the variant peptides did not improve the antimicrobial activity, and there was no statistically significant correlation between any of these factors and the MIC for Pseudomonas aeruginosa, Escherichia coli, or Salmonella typhimurium. Individual peptides demonstrated synergy with conventional antibiotics against antibiotic-resistant strains of P. aeruginosa. The peptides varied considerably in the ability to bind E. coli O111:B4 lipopolysaccharide (LPS), and this correlated significantly with their antimicrobial activity and ability to block LPS-stimulated tumor necrosis factor and interleukin-6 production. In general, the peptides studied here demonstrated a broad range of activities, including antimicrobial, antiendotoxin, and enhancer activities.
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PMID:Biological properties of structurally related alpha-helical cationic antimicrobial peptides. 1008 49

Antibiotic-induced release of endotoxin (lipopolysaccharide, LPS) from Pseudomonas aeruginosa was investigated in in vitro with different antibiotic concentrations and in the pharmacokinetic autosimulation system. We compared the effect of isepamicin (ISP) with those of 3 beta-lactam antibiotics, piperacillin (PIPC), ceftazidime (CAZ) and imipenem (IPM). ISP showed a strong bactericidal activity, but the amount of free LPS did not increase by 6 hrs (28 +/- 2 ng/ml at 1MIC). PIPC and CAZ caused a gradual killing and a large amount of LPS release at 4 hrs (515 ng/ml and 493 ng/ml, respectively, at 1 MIC). At 1/4 x MIC, PIPC and CAZ did not reduce colony forming counts and induced more release of free LPS. The organism treated with IPM released less LPS, while it was killed rapidly. The viable cell counts decreased dramatically after administration of ISP in the pharmacokinetic autosimulation system. ISP inhibited the bacterial regrowth and the following release of free LPS by 8 hrs. Great amounts of free LPS were released 4 hrs after the administration of PIPC and CAZ in the simulation system, associated with morphological changes; elongation, cell lysis or regrowth. IPM showed a strong bactericidal activity and less liberation of free LPS, but the free LPS level increased at 8 hrs, accompanied by the regrowth of the organism. The total amounts of LPS released by P. aeruginosa PAO1 in 8 hours of the pharmacokinetic simulation system were as follows; ISP < IPM < CAZ < PIPC.
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PMID:[Effects of isepamicin and beta-lactam antibiotics on the release of endotoxin from Pseudomonas aeruginosa]. 1020 87

The tight packing of six fatty acids in the lipid A constituent of lipopolysaccharide (LPS) has been proposed to contribute to the unusually low permeability of the outer membrane of gram-negative enteric bacteria to hydrophobic antibiotics. Here it is shown that the Escherichia coli msbB mutant, which elaborates defective, penta-acylated lipid A, is practically as resistant to a representative set of hydrophobic solutes (rifampin, fusidic acid, erythromycin, clindamycin, and azithromycin) as the parent-type control strain. The susceptibility index, i.e., the approximate ratio between the MIC for the msbB mutant and that for the parent-type control, was maximally 2.7-fold. In comparison, the rfa mutant defective in the deep core oligosaccharide part of LPS displayed indices ranging from 20 to 64. The lpxA and lpxD lipid A mutants had indices higher than 512. Furthermore, the msbB mutant was resistant to glycopeptides (vancomycin, teicoplanin), whereas the rfa, lpxA, and lpxD mutants were susceptible. The msbB htrB double mutant, which elaborates even-more-defective, partially tetra-acylated lipid A, was still less susceptible than the rfa mutant. These findings indicate that hexa-acylated lipid A is not a prerequisite for the normal function of the outer membrane permeability barrier.
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PMID:Outer membrane permeability barrier in Escherichia coli mutants that are defective in the late acyltransferases of lipid A biosynthesis. 1034 70

The occurrence of active efflux and cell wall modifications were studied in Salmonella enterica serovar Typhimurium mutants that were selected with enrofloxacin and whose phenotypes of resistance to fluoroquinolones could not be explained only by mutations in the genes coding for gyrase or topoisomerase IV. Mutant BN18/21 exhibited a decreased susceptibility to ciprofloxacin (MIC = 0.125 microg/ml) but did not have a mutation in the gyrA gene. Mutants BN18/41 and BN18/71 had the same substitution, Gly81Cys in GyrA, but exhibited different levels of resistance to ciprofloxacin (MICs = 2 and 8 microg/ml, respectively). None of the mutants had mutations in the parC gene. Evidence for active efflux was provided by a classical fluorimetric method, which revealed a three- to fourfold decrease in ciprofloxacin accumulation in the three mutants compared to that in the parent strain, which was annulled by addition of the efflux pump inhibitor carbonyl cyanide m-chlorophenylhydrazone. In mutant BN18/71, a second fluorimetric method also showed a 50% reduction in the level of accumulation of ethidium bromide, a known efflux pump substrate. Immunoblotting and enzyme-linked immunosorbent assay experiments with an anti-AcrA antibody revealed that the resistance phenotype was strongly correlated with the expression level of the AcrAB efflux pump and suggested that decreased susceptibility to ciprofloxacin due to active efflux probably related to overproduction of this pump could occur before that due to gyrA mutations. Alterations were also found in the outer membrane protein and lipopolysaccharide profiles of the mutants, and these alterations were possibly responsible for the decrease in the permeability of the outer membrane that was observed in the mutants and that could act synergistically with active efflux to decrease the level of ciprofloxacin accumulation.
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PMID:Evidence for active efflux as the primary mechanism of resistance to ciprofloxacin in Salmonella enterica serovar typhimurium. 1077 Jul 55

A murine monoclonal antibody (MAb) specific for the Pseudomonas aeruginosa immunotype 1 (It-1) lipopolysaccharide (LPS) O-side chain was evaluated in terms of its in vitro bactericidal opsonophagocytic activity and in vivo bacterial killing in a mouse thigh infection model. An immunoglobulin (Ig) G2a MAb Ld3-2F2, specific for It-1 LPS, mediated in vitro complement-dependent opsonophagocytic killing at a concentration of 10 microg/ml. MAb-mediated, complement-dependent killing also occurred in the absence of neutrophils at serum concentrations in excess of 20%. A remarkable synergy was observed in opsonophagocytic assays between MAb Ld3-2F2 (0.5 microg/ml) and ceftazidime (1/4 MIC). The administration of MAb Ld3-2F2 at a level of 1 microg resulted in a significant decrease in the number of bacteria in the thigh muscles of normal mice, while 100 microg of the same MAb was required for one log of reduction in the number of bacteria at the same site in neutropenic mice. The combined therapy with MAb Ld3-2F2 and ceftazidime provided a significant reduction in the density of bacteria in the thigh muscle at 9 hr post-infection in normal and neutropenic mice as compared with those after treatment alone or with no treatment (P< 0.01). These favorable in vitro and in vivo interactions of an LPS-specific IgG MAb and ceftazidime strongly support their potential for use in therapy, combined with an LPS-reactive MAb and parenteral antipseudomonas beta-lactam antibiotics in the therapy of systemic Pseudomonas infections in normal and neutropenic hosts.
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PMID:Antibacterial properties of Pseudomonas aeruginosa immunotype 1 lipopolysaccharide-specific monoclonal antibody (MAb) in a murine thigh infection model: combined effects of MAb and ceftazidime. 1102 92

Our objective was to determine whether strains of Pseudomonas aeruginosa can adapt to growth in increasing concentrations of the disinfectant benzalkonium chloride (BKC), and whether co-resistance to clinically relevant antimicrobial agents occurs. Attempts were made to determine what phenotypic alterations accompanied resistance and whether these explained the mechanism of resistance. Strains were serially passaged in increasing concentrations of BKC in static nutrient broth cultures. Serotyping and genotyping were used to determine purity of the cultures. Two strains were examined for cross-resistance to other disinfectants and antibiotics by broth dilution MIC determination. Alterations in outer membrane proteins and lipopolysaccharide (LPS) expressed were examined by SDS-PAGE. Cell surface hydrophobicity and charge, uptake of disinfectant and proportion of specific fatty acid content of outer and cytoplasmic membranes were determined. Two P. aeruginosa strains showed a stable increase in resistance to BKC. Co-resistance to other quaternary ammonium compounds was observed in both strains; chloramphenicol and polymyxin B resistance were observed in one and a reduction in resistance to tobramycin observed in the other. However, no increased resistance to other biocides (chlorhexidine, triclosan, thymol) or antibiotics (ceftazidime, imipenem, ciprofloxacin, tobramycin) was detected. Characteristics accompanying resistance included alterations in outer membrane proteins, uptake of BKC, cell surface charge and hydrophobicity, and fatty acid content of the cytoplasmic membrane, although no evidence was found for alterations in LPS. Each of the two strains had different alterations in phenotype, indicating that such adaptation is unique to each strain of P. aeruginosa and does not result from a single mechanism shared by the whole species.
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PMID:Pseudomonas aeruginosa cells adapted to benzalkonium chloride show resistance to other membrane-active agents but not to clinically relevant antibiotics. 1190 37

Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an Escherichia coli strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the alpha-(R)-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the Enterobacteriaceae, Serratia marcescens, Morganella morganii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia cepacia. BB-78484 was bactericidal against E. coli, achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis. E. coli mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the fabZ or lpxC genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.
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PMID:Antibacterial activities and characterization of novel inhibitors of LpxC. 1201 92

This study was designed to compare the amount of lipopolysaccharide (LPS) induced following exposure to doripenem, imipenem/cilastatin, meropenem and ceftazidime in an in vitro computerized-simulation system (simulating the drug concentration pattern in human plasma after administration of a drug), with that induced by exposure to a drug at a constant concentration. When Pseudomonas aeruginosa was exposed to the test drugs at constant concentrations of 0.1 x, 1 x and 10 x MIC, differential relative induction of LPS was observed as follows: ceftazidime > meropenem, doripenem > imipenem/cilastatin. In the computerized-simulation system, however, the amount of LPS induced by treatment with ceftazidime (1 g) was similar to that by doripenem (250 mg), imipenem/cilastatin (500 mg) and meropenem (500 mg). In a rat model of P. aeruginosa bacteraemia, rates of eradication of bacteria from the blood were similar for carbapenems and ceftazidime except for 1 h post-administration of ceftazidime. Serum LPS levels induced by treatment with doripenem (30 mg/kg), imipenem/cilastatin (30 mg/kg), meropenem/cilastatin (30 mg/kg) and ceftazidime (50 mg/kg) were almost the same at 3 h after administration of each drug. Data obtained from computerized-simulation systems might be more applicable than those obtained from organisms exposed to constant drug concentrations for estimating the amount of LPS in the plasma of human patients infected with Gram-negative bacteria.
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PMID:Antimicrobial-induced release of endotoxin from Pseudomonas aeruginosa: comparison of in vitro and animal models. 1256 2

Serotyping is one of the most used techniques for typing Pseudomonas aeruginosa strains. During chronic infections, and especially in cystic fibrosis, the decrease of lipopolysaccharide production is responsible for difficulties in determining O antigens. The possibility of serotyping can be simply restored by using a primary culture broth containing amikacin (1/6 of the strain MIC for this antibiotic); this is due to the ability of this antibiotic to inhibit alginate production. This technique allowed us to determine the serotype of 108 non-serotypable strains of P. aeruginosa isolated in 14 different hospitals. Among these isolates, serotype O:1 and O:13, had a high prevalence; the origin is a deficiency in D-glucose and L-rhamnose, required for the synthesis of lipopolysaccharide. In contrast, these sugars are not present in lipopolysaccharide of O:12, and these strains are always serotypable. The main protein is Alg C; this bifunctional enzyme is required in the exopolysaccharide and lipopolysaccharide production, according stress conditions in the bacterial-cells' environment. Determination of the serotype, as Antibiogram, is essential for genotypic inquiries.
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PMID:[Recovery method of serotypable character in non serotypable pseudomonas aeruginosa strains]. 1476 11

By screening for high-level mecillinam resistant derivatives of a low-level resistant strain (cysB403 galE1922 relA21::Tn10) of Salmonella enterica serovar Typhimurium, a MudJ insertion in the gene for soluble lytic transglycosylase (slt) was isolated. This insertion (slt-1::MudJ) increased the resistance to mecillinam of cysB and cysE strains (MIC: about 20-40 microg mL(-1)) to a strikingly high level (MIC: 160 microg mL(-1)). As in Escherichia coli K-12, the slt mutation slightly increased the sensitivity of the wild type and of several strains that carried mutations that did not increase mecillinam resistance. All the strains acquired a spherical cell shape when treated with mecillinam. The effect of slt-1::MudJ was limited to mecillinam, the response to several other antibiotics remaining unaltered by the insertion. The results presented in this paper demonstrate that soluble lytic transglycosylase performs an important role in the response to mecillinam, which only becomes evident when failure of CysB/CysE function causes medium-level resistance. The results also suggest that soluble lytic transglycosylase interacts with, and is partially inhibited by normal lipopolysaccharide.
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PMID:High-level resistance to mecillinam produced by inactivation of soluble lytic transglycosylase in Salmonella enterica serovar Typhimurium. 1649 22


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