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Polymyxin-resistant pmrA strains were shown to absorb only about 25% of the amount of polymyxin absorbed by the corresponding polymyxin-sensitive parent strains. The lipopolysaccharide from the pmrA strains bound less polymyxin than the lipopolysaccharide from the parent strains.
A complex of polymyxin B, bovine serum albumin, and colloidal gold was prepared and used for the ultrastructural localization of polymyxin B binding sites on thin sections of Epon-embedded Escherichia coli cells. Gold particles were found on the outer membrane of E. coli, which is consistent with reported biochemical findings. We concluded that gold labeling with polymyxin B is useful in localizing the binding sites of polymyxin.
BACKGROUND: Intraocular inflammation is typically treated with a combination of anti-inflammatory and anti-infective drugs. Tobramycin-dexamethasone (TD) has not been associated with any serious adverse events, indicating good tolerability. OBJECTIVE: The aims of this study were the following: (1) to demonstrate noninferiority of TD compared with dexamethasone-neomycin-polymyxin (DNP) in terms of anti-inflammatory efficacy, (2) to compare the anti-inflammatory efficacy of TD and DNP with that of a "placebo" control (antibiotic without anti-inflammatory agent), and (3) to provide additional safety data on TD. METHODS: This prospective, double-masked, parallel-group study was conducted at 22 ophthalmology clinics across Europe and Brazil. Patients aged > 18 years undergoing cataract surgery were randomly assigned, in a 2:2:1 ratio, to receive tobramycin 3 mg/mL plus dexamethasone 1 mg/mL, dexamethasone 1 mg/mL plus neomycin sulfate 3500 IU/mL plus polymyxin B sulfate 6000 IU/mL, or neomycin sulfate 3500 IU/mL plus polymyxin B sulfate 7500 IU/mL plus gramicidin 20 microg/mL. All treatments were given as 1 drop instilled in the operated eye q.i.d. for 21 days. The primary efficacy end point, intraocular inflammation (determined using the sum of scores on anterior chamber cells and aqueous flare), was assessed at days 3, 8, 14, and 21 after surgery. RESULTS: A total of 271 patients were enrolled (158 women, 113 men; age range 42-90 years) (TD, 104 patients; DNP, 110 patients; and neomycin-polymyxin-gramicidin [NPG], 57 patients). Intraocular inflammation was similar in the TD and DNP groups at all time points. At days 8, 14, and 21, inflammation scores were significantly lower with TD than with NPG (all, P < 0.05). At day 8, the inflammation score was significantly lower with DNP than with NPG (P < 0.05). A greater number of patients receiving NPG experienced treatment-related ocular allergic reactions compared with patients receiving TD (P < 0.05). One patient receiving TD (1.0%) and 5 given NPG (9.0%) were withdrawn due to ocular allergic reactions. None of the patients experienced an increase in intraocular pressure > or =10 mm Hg from baseline. CONCLUSIONS: In this study of patients undergoing cataract surgery combination therapy with TD was noninferior to DNP and was well tolerated.
An eight-laboratory study addressed the urgent need for quality control (QC) ranges for susceptibility determination when testing colistin (polymyxin E) and polymyxin B, two polycationic peptide antimicrobial agents, against multidrug-resistant gram-negative bacilli. For Escherichia coli ATCC 25922l, the QC ranges were as follows: for colistin, 0.25 to 1 microg/ml (11 to 17 mm), and for polymyxin B, 0.25 to 2 microg/ml (13 to 19 mm). For Pseudomonas aeruginosa ATCC 27853, the QC ranges were as follows: for colistin, 0.25 to 2 microg/ml (11 to 17 mm), and for polymyxin B, 0.25 to 2 mug/ml (14 to 18 mm). More than 97% of all reported QC results were within these proposed ranges.
Spatial structure of polypeptide antibiotic polymyxin M in water was studied by one-and two-dimensional (COSY, COSY-45, RELAY) H NMR spectroscopy. Analysis of the signal spectral parameters revealed two intramolecular hydrogen bonds in the cyclic part of the molecule which was analogous to the structure of polymyxin B. However, configuration of both the beta-turns in the polymyxin M structure differed from that of the detected earlier beta-turns in the structure of polymyxin B.
The sensitivity of 12 strains of Pseudomonas aeruginosa and of 12 strains of Proteus species to co-trimoxazole, polymyxins and combinations of co-trimoxazole and polymyxins was determined by disc and tray methods. It was found that all strains were sensitive to the combinations of co-trimoxazole and polymyxins. The disc study of the strains of Ps. aeruginosa revealed a typical image with many strains. The tray study gave a typical image with two strains of Proteus species. The two images are briefly discussed. The synergistic action of co-trimoxazole and polymyxins may well offer therapeutic possibilities.
Polymyxin B and its shortened analog were studied comparatively by 1H-NMR spectroscopy. Analysis of the signal chemical shifts, constants of spin-spin interaction of 3J HN-C alpha H and temperature coefficients of the NH signal chemical shifts revealed absolute structural identity of both molecules cyclic parts. This proved that there was no conformative interaction between the cyclic and linear parts of the polymyxin B molecule. Comparison of the results with the data on the biological activity showed that the hydrophobic N-end moiety of the polymyxin B molecule played a specific role in its antibacterial effect and toxicity.
Lipopolysaccharides isolated from the polymyxin-resistant Klebsiella pneumoniae O3 mutant OM-5 and its polymyxin-sensitive parent LEN-1 were analyzed for chemical composition, and their lipid A portions were structurally characterized. The lipopolysaccharide of OM-5 contained approximately five times more 4-amino-4-deoxy-L-arabinopyranose than that of LEN-1. Other saccharide and phosphate components exhibited no significant differences. Structural characterization, including analyses by phosphorus magnetic resonance spectroscopy and by fast atom bombardment mass spectrometry, revealed a novel type of lipid A. In the OM-5 lipopolysaccharide, both phosphates of lipid A were almost totally present as phosphodiesters with 4-amino-4-deoxy-L-arabinopyranose. In the sensitive-type LEN-1 lipid A, the extent of this substitution was much lower, especially in the glycosidically linked phosphate. Phosphate in these K. pneumoniae lipopolysaccharides was almost exclusively found in lipid A. These results show that cationic substituents of phosphates of lipid A play a decisive role in determining polymyxin reactivity. OM-5 was also found to contain a large proportion of heptaacyl lipid A, which represented only a small fraction of lipid A in LEN-1.
Polymyxin B octapeptide (PBOP) and polymyxin B heptapeptide (PBHP) were found to be effective permeabilizers of the outer membrane of Escherichia coli and Salmonella typhimurium. PBOP was as effective as polymyxin B nonapeptide (PMBN), the known very potent permeabilizer. As low a PBOP concentration as 1 microgram/ml sensitized E. coli to rifampicin by a factor of 100. Three micrograms of PBOP per ml was sufficient to sensitize this target to all the other tested hydrophobic antibiotics (erythromycin, fusidic acid, clindamycin, and novobiocin) by a factor of 30. Only a slightly higher (3-fold) concentration of PBHP was required for a similar sensitizing effect.
A polymyxin-B/bovine-serum-albumin/gold complex was used as a probe to detect the binding sites of polymyxin B on thin sections of cochlea embedded in Spurr's resin. The binding sites were found to be mainly located on the stereocilia, the cuticular plate of hair cells, the head plate of Deiters' cells, the tonofilaments in pillar cells and Deiters' cells, fibrous structures in the spiral limbus, the tectorial membrane and the basilar membrane and neural elements such as nerve endings, fibers, and the myelin sheath. The mitochondria, plasma membrane, and chromatin of the nuclei of the cells observed also exhibited binding. Our results suggest that phospholipids, glycoconjugates, cytoskeletal proteins and nucleic acids are responsible for this binding activity.
Long chain spin labels with the nitroxide group located near the terminal methyl of the chain were used to determine the percentage interdigitated lipid in complexes of polymyxin B (PMB) and polymyxin B nonapeptide (PMBN) with the acidic lipids dipalmitoylphosphatidylglycerol (DPPG) and dipalmitoylphosphatidic acid (DPPA) at varying mole ratios of drug to lipid and at different pH values. These spin labels are more motionally restricted in the interdigitated than in the non-interdigitated gel phase bilayer. This allows determination of the percentage interdigitated lipid by resolution of the spectrum into motionally restricted and more mobile components. At nonsaturating concentrations of PMB, significantly more DPPG than that which can be maximally PMB-bound, becomes interdigitated. As the temperature approaches the gel to liquid crystalline phase transition temperature, the bilayer becomes progressively non-interdigitated. The ESR spectrum indicates that PMB also causes interdigitation of DPPA. However, in contrast to DPPG, the amount of DPPA which is interdigitated at pH 6, is less than the amount which is expected to be PMB-bound. This is attributed to the ability of DPPA to participate in lateral interlipid hydrogen bonding interactions. Such lateral interactions would be abolished in the interdigitated bilayer and thus they are expected to inhibit its formation. At pH 9, where the interlipid interactions of DPPA are weakened, PMB induces even more lipid than that which is PMB-bound to become interdigitated. Indeed, the percentage interdigitated lipid is even greater than found for DPPG. This may be partly a result of the greater negative charge of DPPA at this pH. A greater repulsive negative charge is expected to favor interdigitation. PMBN is less effective than PMB at inducing interdigitation of DPPG and causes little or no interdigitation of DPPA at pH 6, even at saturating concentrations. PMBN also does not lower the phase transition temperature of DPPA at pH 6 as much as PMB. At pH 9, the effect of PMBN on DPPA is more similar to the effect of PMB. However, even for DPPG, and DPPA at pH 9, PMBN does not maintain interdigitation of the lipids at higher temperatures as effectively as PMB. PMBN's smaller perturbing effect and greatly decreased ability to cause interdigitation of DPPA at pH values below 9 may be related to a decreased ability to cause lateral separation of the lipid molecules, which is necessary in order to weaken the interlipid interactions.(ABSTRACT TRUNCATED AT 400 WORDS)
The addition of polymyxin B sulphate (PBS), or an inactive by-product, polymyxin B nonapeptide (PBN) to a yeast bioassay system, increased its sensitivity to various toxic agents. The nil effect level (NEL) of T-2 toxin was reduced from 0.1 to 0.01 microgram/ml for Kluyveromyces fragilis GK 1005 in the presence of these agents when using a Malthus AT 192 conductimetric instrument. Other synergistic agents (DMSO, ethanol, cetyl trimethyl ammonium bromide and Triton X-100) gave poor results in the conductimetric system. PBN also increased sensitivity of K. fragilis GK 1005 towards cycloheximide in the Malthus system, and PBS reduced the NEL of T-2 toxin for K. fragilis GK 1005 in a disc diffusion assay from 0.2 to 0.04 microgram per disc. No yeasts were found sensitive to the trichothecene deoxynivalenol (DON) even at a DON concentration of 10 micrograms/ml, except in the presence of PBN and PBS. The minimal inhibitory concentration (mic) of DON in the presence of PBS was 2 micrograms/ml for K. fragilis GK 1005.
Two polymyxin antibiotics, polymyxins B and E (colistin), have been separated analytically into ten to thirteen components on a commercial reversed-phase material by isocratic elution with a mixture of acetonitrile, phosphate/formate and acetate buffer containing sodium sulphate and triethylamine. The analytical system was transferred to a preparative system, using a C18-bonded stationary phase, without extensive impairing of the selectivity. The major components of each product were isolated and characterized by high-performance liquid chromatography, amino acid analysis and identification of the fatty acid. Three components were isolated and characterized for the first time. The fatty acid was also identified in some of the minor components.
This was a double-blind randomized study to compare the safety and efficacy of trimethoprim-polymyxin B (TP) and trimethoprim-sulfacetamide-polymyxin B (TSP) drops in the treatment of otorrhea. The 68 cases treated suffered from external otitis, recurrent otitis media with tympanic membrane perforation, or infected mastoid cavities and post-operative tympanoplasties. The TP ototopical solution was successful in 60.6 per cent of cases compared to 88.6 per cent of cases with TSP. These rates were statistically different using the Chi Square with Yates' correction method. There were no signs of ototoxicity, fungal infection overgrowth or local sensitivity to either of the solutions. The study has shown that both drugs are equally safe and that TSP is significantly more effective in the treatment of otorrhea.
The purpose of his double-blind, randomized trial was to compare ear drops containing either trimethoprim and polymyxin B (TP) or trimethoprim, sulphacetamide and polymyxin B (TSP) from the points of view of effectiveness and safety. The 68 patients treated had otitis externa or recurrent otitis media with perforated ear-drum, or mastoid cavity with post-tympanoplasty infection. Satisfactory results were obtained in 60.6% of the cases with TP and in 88.6% with TSP. When evaluated by the Chi-square method with Yates' correction, the difference was statistically significant. There was no evidence of ototoxicity, fungal infection or local hypersensitivity with either preparation. The trial demonstrated that both ear drops were active and that TSP was much more effective than TP in the treatment of otorrhea.
We previously reported that polymyxin B (PMB) enhances cellular catabolism of low density lipoproteins (LDLs) through a non-LDL receptor-mediated endocytotic pathway. These data were obtained mainly by using Hep G2 cells, a well differentiated human hepatoma cell line. In the current study, we explore the mechanisms of PMB-mediated endocytotic catabolism of LDL. We found that PMB enhanced LDL catabolism also in homozygous familial hypercholesterolemia fibroblasts, thereby establishing that PMB-mediated cellular catabolism of LDL does not involve LDL receptors. By using [14C]sucrose, and ligands for the asialoglycoprotein (ASGP) receptors, possibilities were excluded that PMB enhances cellular endocytosis of LDL, by inducing a general increase of cellular pinocytic activity or by causing endocytosis of LDL via the ASGP receptors in Hep G2 cells. We further show, by using polymyxin B coupled Sepharose 4B (PMB-Sepharose 4B) beads, that PMB binds to LDL to form a complex. This binding was tight, and changes in pH and salt concentrations had no significant effect on the binding, but unlabelled LDL competed with 125I-LDL to bind to PMB-Sepharose 4B. Urea and endotoxins decreased this binding, suggesting that PMB binds to LDL at least partially through hydrophobic interactions. Agarose gel electrophoresis of PMB-LDL indicates that PMB cationizes LDL. In conclusion, PMB binds to LDL to form a PMB-LDL complex presumably through interactions between lipid groups. This endows LDL with positive charges, which enhances LDL binding to negatively charged cell membranes, and such bound LDL is rapidly internalized through absorptive endocytosis.
The Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is a major inducer of sepsis. The natural cyclic peptide polymyxin B (PMB) is a potent antimicrobial agent, albeit highly toxic, by virtue of its capacity to neutralize the devastating effects of LPS. However, the exact mode of association between PMB and LPS is not clear. In this study, we have synthesized polymyxin B nonapeptide, the LPS-binding cyclic domain of PMB, and its enantiomeric analogue and studied several parameters related to their interaction with LPS and their capacity to sensitize Gram-negative bacteria toward hydrophobic antibiotics. The results suggest that whereas the binding of the two enantiomeric peptides to E. coli and to E. coli LPS is rather similar, functional association with the bacterial cell is stereospecific. Thus, the L-enantiomer is capable of synergism with the hydrophobic antimicrobial drugs novobiocin and erythromycin, whereas the D-enantiomer is devoid of such activity. The potential of understanding and consequently utilizing the PMB-LPS association for novel, nontoxic PMB-derived drugs is discussed.
48 patients witha diagnosis of presumptive bacterial conjunctivitis were assessed. They had been treated with either trimethoprim-polymyxin or neomycin-polymyxin-gramicidin eye drops in a randomised double-blind trial. There were 24 patients in each treatment group. There were no significant differences between the two preparations proved with regard to the eradication of organisms or clinical improvement, and both preparations proved to be very effective. Patient compliance was good and no adverse reactions were encountered with either preparation.