Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0519030 (Klebsiella)
 21,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When genetically serum-resistant Escherichia coli, Klebsiella pneumoniae, and Citrobacter freundii, but not Pseudomonas aeruginosa or Proteus mirabilis, were exposed to polymyxin B, they became susceptible to the bactericidal action of normal human and rabbit sera. In constrast, beta-lactam and aminoglycoside antibiotics did not render any serum-resistant bacteria serum-sensitive. Synergy between polymyxin B and the serum bactericidal system could be demonstrated by the addition of polymyxin B to bacteria in vitro, as well as to bacilli in serum from rabbits injected with the antibiotic. Polymyxin B-treated bacteria were killed by normal, lysozyme-depleted, C2-deficient, and hypogammaglobulinemic sera, but not by heated or C6-deficient sera. These findings indicate that polymyxin B-treated bacteria can be killed via the alternative complement pathway. However, C3 and C3b were detected on the surface of serum-resistant E. coli, regardless of whether the bacteria had been treated with polymyxin B. This observation suggests that a change in susceptibility to the alternative complement pathway was not the only explanation for the acquired serum sensitivity. Polymyxin B may also affect a step in the complement sequence beyond the activation of C3, a step that is apparently blocked in serum-resistant gram-negative bacteria.
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PMID:Lethal effect of complement and lysozyme on polymyxin-treated, serum-resistant gram-negative bacilli. 22 75

The peptide antibiotic Polymyxin B (PMB) binds to bacterial endotoxin (lipopolysaccharide, LPS). We prepared covalent conjugates of PMB and horseradish peroxidase (HRP) by periodation of HRP-linked oligosaccharides followed by direct condensation with PMB. In addition we prepared monoclonal antibodies (Mabs) to PMB. The PMB-HRP conjugates and anti-PMB Mabs were used to study in ELISA the binding of PMB to LPS from Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In addition, PMB-HRP was used to quantify lipid A in ELISA, and to stain gram-negative bacteria histochemically. For the study of PMB-LPS interaction, PMB-HRP proved to be superior to the anti-PMB Mabs. PMB-HRP conjugates are useful general probes to detect or measure lipid A and LPS of various species using very simple methods and to stain bacteria, and they may obviate the need for many specific antisera. Thus, PMB-HRP conjugates are useful probes for endotoxin research.
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PMID:Polymyxin B-horseradish peroxidase conjugates as tools in endotoxin research. 148 86

RU41740 is a glycoprotein extract from Klebsiella pneumoniae with immunomodulating properties under different experimental conditions. In particular the compound is able to stimulate several functions of human phagocytes in vitro and ex vivo. Using monoclonal antibodies and flow cytometry, in this work we assessed the effect of RU41740 on surface expression of receptors for C3b (CR1) and C3bi (CR3) in human phagocytic cells in vitro. The incubation of whole blood with varying RU41740 concentrations led to a dose-dependent increase in surface expression of CR1 and CR3 on both neutrophils and monocytes when compared with control samples incubated in buffer alone. The maximal drug-induced enhancement of complement receptors was: 291% +/- 13.4% for CR1 and 265% +/- 8.5% for CR3 in neutrophils; 117% +/- 4.5% for CR1 and 98% +/- 4.1% for CR3 in monocytes. These peak effects were observed using RU41740 at a final concentration of 10 micrograms/ml and were similar to those induced by optimal concentrations of the activating compound N-formyl-methionyl-leucyl-phenylalanine (10(-7)M). Polymyxin B did not modify the RU41740-induced enhancement of CR1 and CR3 expression on phagocytes, suggesting no role for endotoxin in this activity. These results define, at least in part, the mechanism of action of RU41740 on human phagocytes in vitro and could be relevant to in vivo events during RU41740 treatment.
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PMID:Increased expression of C3b and C3bi receptors on human neutrophils and monocytes induced by a glycoprotein extract from Klebsiella pneumoniae (RU41740). 183 41

Polymyxin B nonapeptide was able to sensitize Escherichia coli strains and strains of Salmonella typhimurium, Klebsiella spp., Enterobacter cloacae, Pseudomonas aeruginosa, and Haemophilus influenzae to the bactericidal action of fresh normal human serum. The degree of sensitization varied significantly within the strains. Strains of Proteus mirabilis, Neisseria gonorrhoeae, and N. meningitidis remained resistant.
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PMID:Susceptibility of gram-negative bacteria to the synergistic bactericidal action of serum and polymyxin B nonapeptide. 300 71

The udders of 100 heifers were examined for clinical changes during parturition. Of each quarter colostral samples were taken and analyzed bacteriologically. 35 heifers (13.5% of the quarters) showed clinical changes of the quarters and/or of colostral samples. 14 of these animals (4.75% of the quarters) suffered from cellulitis-like mastitis. 13 (5.25% of the quarters) had acute catarrhalic mastitis and eight heifers (3.5% of the quarters) showed acute galactophoritis. In all milk samples of animals with pathological changes of the udder or of colostrum the causing bacteria could be identified. Besides the group of 35 heifers with clinical lesions udder-pathogenic bacteria were found in samples of 24 apparently healthy animals (20.5% of the quarters) during parturition. However, these animals failed to show clinical signs of inflammation at least until the end of this study (10 days post partum). Isolated bacteria included facultative and obligate pathogenic species, 70% of which were gram-positive cocci (i.e. Streptococcus [Sc.] uberis, Sc. dysgalactiae, Sc. agalactiae, Staphylococcus aureus and other staphylococci) versus 30% of gram-negative bacteria (i.e. Escherichia [E.] coli, Klebsiella and other coliform species. In-vitro-susceptibility tests showed best effectiveness of Penicillin against Sc., Cloxacillin against staphylococci and Gentamycin and Polymyxin B against coliform bacteria. Possible pathways, leading to bacterial infection of first lactating heifers during parturition, are discussed. Pathways of infection seem to be of lesser importance for the development of apparent, sometimes severe mastitis with coliform bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Clinical and bacteriologic studies of the frequency of mastitis during and after parturition in heifers lactating for the first time]. 305 22

Two mechanisms of direct activation of the complement system by LPS have been extensively documented: (i) activation of the alternative pathway (AP) by the polysaccharide region, and (ii) activation of the classical pathway (CP) by the lipid A region. Here we demonstrate that LPS from the Klebsiella pneumoniae I-145 strain activates the AP by a mechanism dependent on the acylation of the lipid A region. Cleavage of C3 by K. pneumoniae LPS in EGTA was blocked by polymyxin B. Two 34 kDa derivatives were prepared from a membrane extract of this K. pneumoniae strain: (i) an acyl-poly (1,3) galactoside containing two galactosamine-bound ester-linked and two amide-linked fatty acids (EFA-APG), and (ii) an acyl-poly (1,3) galactoside devoid of ester-linked fatty acids (APG). APG and EFA-APG share the structure of LPS molecules, with a long polysaccharidic chain, a core, and a lipid A region. The AP was activated by EFA-APG but not by APG nor by the isolated polygalactose chain GC-APG, indicating a critical role for ester-linked fatty acids in AP activation. Polymyxin B which binds to the lipid A region of LPS completely inhibited AP activation by EFA-APG. A small part of EFA-APG was shown to form aggregates in saline, but aggregation was not decreased by polymyxin B. Furthermore, APG formed aggregates of similar size although it was not able to activate AP. Therefore the role of lipid A acylation in triggering AP activation is not exclusively mediated by aggregation of the molecule. LPS from the rough strain of Salmonella minnesota (Sm Re LPS) directly activates the CP but not the AP. However, when mixed with the polygalactose chain GC-APG, Sm Re LPS activated the AP. The data demonstrate a cooperation between the lipid A region and the polysaccharidic chain in activation of the AP. Similar cooperation may occur with other LPS molecules.
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PMID:Acylation of the lipid A region of a Klebsiella pneumoniae LPS controls the alternative pathway activation of human complement. 796 85

Polymyxin B (PMB) is a cyclic decapeptide antibiotic which also binds and neutralizes endotoxin. Unfortunately, PMB can be considerably nephrotoxic at clinically utilized doses, thereby limiting its utility as a therapeutic antiendotoxin reagent. We sought to change the pharmacokinetics and toxicity profile of PMB by covalently linking it to a human immunoglobulin G (IgG) carrier. Conjugates of PMB with IgG were prepared by EDAC [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide]-mediated amide formation. Analysis by dot enzyme-linked immunosorbent assay with an anti-PMB monoclonal antibody showed that the purified conjugate contained bound PMB. The IgG-PMB conjugate reacted with lipid A and J5 lipopolysaccharide in Western blot assays in a manner comparable to that of whole antiserum with anti-lipid A reactivity; unconjugated IgG had no reactivity. The PMB bound in the conjugate retained its endotoxin-neutralizing activity compared to that of unbound PMB as evidenced by its dose-dependent inhibition of tumor necrosis factor release by endotoxin-stimulated human monocytes in vitro; unconjugated IgG had no activity. By this assay, the PMB-IgG conjugate was determined to have approximately 3.0 microg of bound functional PMB per 100 microg of total protein of conjugate (five molecules of PMB per IgG molecule). The PMB-IgG conjugate was also bactericidal against clinical strains of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae relative to unconjugated IgG with MBCs of <4 microg of conjugate per ml for each of the tested strains. The conjugate appeared to be nontoxic at the highest doses deliverable and provided statistically significant protection from death to galactosamine-sensitized, lipopolysaccharide-challenged mice in a dose-dependent fashion when administered prophylactically 2 h before challenge. However, neither free PMB nor the PMB-IgG conjugate could protect mice challenged with endotoxin 2 h after administration. This suggests that these reagents can play a role in prophylaxis but not in therapy of sepsis. These experiments demonstrated that the PMB-IgG conjugate retains bound yet functional PMB as evidenced by its endotoxin-neutralizing activity both in vitro and in vivo. Further work is required to define the role that this or related conjugate compounds may play in the prophylaxis of endotoxin-mediated disease.
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PMID:Covalent polymyxin B conjugate with human immunoglobulin G as an antiendotoxin reagent. 951 36

Increasing prevalence of multidrug-resistant gram-negative organisms has led to a rise in clinically significant infections with these organisms and an increasing therapeutic dilemma. We present a case of a neurosurgical patient who developed ventriculoperitoneal shunt-associated ventriculitis due to ceftazidime-resistant Klebsiella pneumoniae susceptible to cefepime, imipenem, meropenem, and polymyxin B only. Successful management was accomplished by removal of the shunt and therapy with systemic meropenem and intraventricular polymyxin B. Rapid cerebrospinal fluid (CSF) sterilization occurred, with CSF bactericidal titers of 1:32 to 1:128. Polymyxin B should be considered as adjunctive therapy for life-threatening multidrug-resistant gram-negative infections. Prior literature on use of intrathecal polymyxin B in therapy for meningitis supports its potential efficacy.
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PMID:Successful treatment of ceftazidime-resistant Klebsiella pneumoniae ventriculitis with intravenous meropenem and intraventricular polymyxin B: case report and review. 1045 48

Polymyxin B nonapeptide (PMBN), a cationic cyclic peptide derived by enzymatic processing from the naturally occurring peptide polymyxin B, is able to increase the permeability of the outer membrane of Gram-negative bacteria toward hydrophobic antibiotics probably by binding to the bacterial lipopolysaccharide (LPS). We have synthesized 11 cyclic analogues of PMBN and evaluated their activities compared to that of PMBN. The synthetic peptides were much less potent than PMBN in their capacity to sensitize Escherichia coli and Klebsiella pneumoniae toward novobiocin and to displace dansyl-PMBN from Escherichia coli LPS. Moreover, unlike PMBN, none of the analogues were able to inhibit the growth of Pseudomonas aeruginosa. The structural-functional features of PMBN were characterized and identified with regard to the ring size, the distance between positive charges and peptide backbone, the chirality of the DPhe-Leu domain, and the nature of the charged groups. Apparently, the structure of PMBN is highly specific for efficient perturbation of the outer membrane of Gram-negative bacteria as well as for LPS binding. The present study further increases our understanding of the complex PMBN-LPS and may, potentially, enable the design of compounds having enhanced permeabilization potency of the Gram-negative outer membrane.
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PMID:Structure-function studies of polymyxin B nonapeptide: implications to sensitization of gram-negative bacteria. 1095 16

The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics to combat them have led to the revival of polymyxins, an old class of cationic, cyclic polypeptide antibiotics. Polymyxin B and polymyxin E (colistin) are the 2 polymyxins used in clinical practice. Most of the reintroduction of polymyxins during the last few years is related to colistin. The polymyxins are active against selected gram-negative bacteria, including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species. These drugs have been used extensively worldwide for decades for local use. However, parenteral use of these drugs was abandoned approximately 20 years ago in most countries, except for treatment of patients with cystic fibrosis, because of reports of common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who received intravenous polymyxins for the treatment of serious P. aeruginosa and Acinetobacter baumannii infections of various types, including pneumonia, bacteremia, and urinary tract infections, have led to the conclusion that these antibiotics have acceptable effectiveness and considerably less toxicity than was reported in old studies.
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PMID:Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. 1582 37


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