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Polymyxin B combined with the resting spores of Bacillus subtilis and inhibited outgrowth and vegetative growth after germination. The antibiotic was released from the resting spores and its inhibitory action was reversed by the addition of di- and trivalent metallic cations.
Growth of the spherule phase of Coccidioides immitis in liquid glucose-mineral salts medium was suppressed for 13 days by 5 to 10 mug of polymyxin B per ml. Inhibition of growth was also noted when filter paper disks containing polymyxin B were placed on the surface of arthrospore-seeded defined medium solidified with refined agar. The antibiotic evidently damaged the cytoplasmic membrane inasmuch as spherules suspended in distilled water containing 10 mug of polymyxin B per ml rapidly lost nucleotides. Leakage of nucleotides was prevented by 0.1 M Ca(2+). The anticoccidioidal activity of amphotericin B (0.02 to 0.08 mug/ml) was enhanced by 2.5 mug of polymyxin B per ml. Colistin (polymyxin E) methanesulfonate did not inhibit spherule growth at concentrations as high as 50 mug/ml. This may be because colistin, though structurally similar to polymyxin B, is not cationic because its gamma-amino groups are masked by methanesulfonate radicals.
Radioactive mono-N-acetyl-14C-polymyxin B or natural polymyxin B are within 60 s absorbed by isolated inner (cytoplasmic) and outer membranes from Salmonella typhimuriumG30. The sigmoidal binding isotherms indicate saturation of inner and outer membranes with approximately 30 and 60 nmoles polymyxin B bound per mg membrane, respectively. Based on the known content of these membranes in lipopolysaccharide, phosphatidylglycerol, cardiolipin and phosphatidylethanolamine, a calculation of the theoretical binding capacities yields almost identical values if lipopolysaccharide, phosphatidylglycerol and cardiolipin are assumed to function as the actual binding sites for the antibiotic in the isolated membranes. The excellent agreement between theoretical evaluation and experimental determination of polymyxin B-binding capacities leaves little doubt that the named anionic compounds are the chemoreceptors for the cationic antibiotic. This is further substantiated by very similar binding and killing kinetics of polymyxin B.
Polymyxin B sulfate diminished the endotoxin-mediated release of human blood neutrophil lysosomal enzymes. Similarly, this antibiotic reduced the endotoxin-induced increase in the neutrophil hexose monophosphate pathway activity as measured by the release of 14CO2 from [l-14C]glucose. Although these effects were seen with therapeutically attainable levels of polymyxin B sulfate, they could not be demonstrated when the cell-endotoxin interaction preceded treatment with polymyxin B sulfate.
Polymyxins are known to be inhibitors of certain polyclonal B cell activators such as lipopolysaccharide and dextransulphate. However, increased specific responses to hapten-coupled mitogens have been reported after the addition of polymyxins to superoptimal conjugate doses. In this paper we have studied the effect of polymyxin B on superoptimal polyclonal doses of lipopolysaccharide. Results similar to those reported for hapten-lipopolysaccharide conjugates were obtained. Polymyxin B was also found to exert adjuvant properties for a primary immune response to sheep erythrocytes and to be a thymus-independent antigen.
To identify the polymyxin receptor molecules in the membranes of living microorganisms, fusion of intact Acholeplasma laidlawii B with lipid vesicles was investigated according to the procedure of Grant and McConnell (1973). The naturally polymyxin-resistant A. laidlawii B was treated with phospholipid vesicles prepared from purified phospholipids of the polymyxin-susceptible Salmonella typhimurium G30. A. laidlawii B absorbed between 15 and 45% of its own lipid content of the added tritium-labeled phospholipids without loss of viability. Association with the acidic components phosphatidylglycerol and cardiolipin produced a 10- to 30-fold increase in polymyxin susceptibility, which was not obtained with egg-phosphatidylcholine and mixed phosphatidylcholine-phosphatidylethanolamine vesicles. The polymyxin-sensitized cells bound 12 times more radioactive antibiotic than resistant cells. The phosphatidylglycerol-induced susceptibility was abolished by serum fraction V (Cohn) proteins.
Effects of polymyxin B on the synthesis and degradation of lipid, ribonucleic acid (RNA) and protein in Pseudomonas aeruginosa were investigated. It was found that polymyxin B caused a marked degradation of the lipid fraction which was prelabeled with (3H-2)-glycerol. Thin-layer chromatographic analysis indicated that the main degraded lipids were phosphatidylethanolamine and phosphatidylglycerol, which constituted 80% and 15% of the total phospholipids of this organism, respectively. Polymyxin B also inhibited synthesis of RNA and protein in vivo. The severe inhibition of the uptake of labeled amino acids by polymyxin B indicated that the observed inhibition of RNA and protein synthesis possibly occurred at the level of substrate transports. The degradation of phospholipid might account for the defective membrane activities.
Neomycin and polymyxin B produce neuromuscular blocks with distinct features by different mechanisms of action. In eight anesthetized cats the authors studied their interaction by examining the neuromuscular block produced by an equipotent mixture. Values of onset, potency, dose-response relations, duration and reversibility of block, the train-of-four and tetanic responses during block, the frequency-block relationships, and the posttetanic twitch behavior were well approximated by averaging the corresponding values previously reported for each antibiotic. Edrophonium, 0.2 mg/kg, reversed the block by 8 to 35 per cent. 4-Aminopyridine, 0.6 mg/kg, completely reversed the block and caused a long-lasting overshoot of the twitch response. The authors conclude that neomycin and polymyxin B are additive in neuromuscular effects, not only in terms of potency and duration, but also in terms of the characteristics of the blocks produced.
Toxicity of Soviet polymyxin B and its effect on the central peripheral nervous system, blood circulation, respiration, smooth muscles, functional liver and kidney state, growth and development of young animals, the picture of the peripheral blood were studied in acute and chronic experiments on various species of animals. It was found that polymyxin B had a suppressing effect on the peripheral n-cholinoreactive systems of the neuromuscle synapses of the skeletal muscles and ganglia of the sympathic and parasympathic innervation and deprimizing effect on the central nervous system. Caffeine, adrenaline and calcium chloride proved to be the antagonists of the neurotoxic effects of polymyxin B. The chronic experiments revealed that polymyxin B induced disorders in the kidney function and morphological changes in the glomeruli after its repeated administration. No significant effect of polymyxin B on the growth and development of the young animals, the functional state of the liver and the picture of the peripheral blood was observed when the drug was used in doses corresponding to the therapeutic ones in clinics.
The effect of a number of the most important amino acids on the growth of B. polymyxa 1538 and polymyxin B biosynthesis was studied. It was found that all of the amino acids tested except D-L-threonin and L-alpha-gamma-DABA inhibited the initial growth of the organism. D-L-threonine and L-alpha-gamma-DABA had some stimulating effect on the culture growth without affecting the final accumulation of the biomass. The antibiotic synthesis proceeded more vigorously when the medium contained D-L-threonine, L-alpha-gamma-DABA, L-asparagine, L-proline, L-glutamine, D-L-asparaginic acid and L-glutamic acid in the concentrations tested. Neither of the tested amino acids used alone or in combination provided the levels of polymyxin B biosynthesis observed on the media containing rich sources of organic nitrogen.
Pharmacokinetics of polymyxin B sulfate of Soviet production was studied in various species of animals with the use of different administration routes and dosage. After a single intramuscular administration of the drug to dogs in doses of 1.1 and 2.2 mg/kg the antibiotic was detected within 5 hours at the maximum level during the 1st hour. A two-fold increase of the dose was accompanied by 1.5 times increase in the antibiotic level. Repeated administrations of polymyxin B sulfate in a dose of 4.5 mg/kg did not result in an increase in the blood level as compared to a single use of the drug. When polymyxin B sulfate was administered intravenously, the concentration peak was observed in 15 minutes independent of the dosage. Later the antibiotic level decreased. The maximum level of the drug in the mice was observed 1 hour after its intramuscular administration in a dose of 8 mg/kg, the highest levels being registered in the kidney tissues and urine.
A patient receiving polymyxin B sulfate intravenously for Gram-negative "anion gap". Both abnormalities resolved following discontinuation of the drug. In vitro investigation suggested that the electrolyte abnormalities resulted from the polycationic properties of polymyxin B.
The site of neuromuscular blockade induced by polymyxin B and rolitetracycline was studied on isolated nerve and nerve-muscle preparations. Polymyxin B (1.8 X 10(-4) M) was equipotent to lidocaine as a local anaesthetic on a frog desheathed nerve preparation, while rolitetracycline (up to 3.6 X 10(-3)M) had no local anaesthetic effect. Polymyxin B (6 X 10(-5) M) and rolitetracycline (7 X 10(-4) M) blocked by 50% the response of rat diaphragm induced by phrenic nerve stimulation, but did not decrease the amount of acetylcholine (ACh) released from this preparation during nerve stimulation. Both antibiotics depressed the response of the rat diaphragm to inject ACh, and this response was more sensitive to inhibition by the drugs than was the response to nerve stimulation. With rolitetracycline, a concentration that blocked the response to nerve stimulation by 50% inhibited the response to injected ACh by 85%, and this relationship was similar to that with d-tubocurarine; however, polymyxin B was relatively more effective than d-tubocurarine in inhibiting the effect of ACh. Polymyxin B (1-1.5 X 10(-4) M) but not rolitetracycline (1 X 10(-3) M) depressed the response of the diaphragm to direct muscle stimulation. It is concluded that polymyxin B and rolitetracycline block neuromuscular transmission predominatly by an effect to depress the muscle's sensitivity to ACh; polymyxin B probably acts by an effect similar to that of local anaesthetics, while rolitetracycline probably acts by an effect similar to that of d-tubocurarine.
In vitro and in vivo complex formations of polymyxin B and lipopolysaccharides (LPS) from resistant and sensitive cells of Serratia marcescens were studied by polyacrylamide gel electrophoresis in sodium dodecyl sulfate and electron microscopy. In vitro treatment of LPS from resistant cells with polymyxin B gave two populations of spherical complexes of differnt molecular weights as determined electrophoretically. Similar treatment of LPS from sensitive cells resulted in dissociation of the LPS-protein and subsequent complexing with the LPS moiety into stable spheres. In vivo treatment of resistant cells with polymyxin B resulted in LPS-polymyxin B complexes which were comparatively smaller and existed in two morphological forms; spheres and linear ribbons. LPS from the sensitive cells were degraded extensively into small rods and an amorphous mass by the in vivo polymyxin B treatment. In both systems, the electrophoretic results consistently matched the electron microscopic evidences for complex formation of LPS with polymyxin B. It is suggested that the disruptive effects of polymyxin B on LPS in the outer membrane of S. marcescens may be the explanation for the change in permeability barrier in the resistant cells and disorganization of the outer membrane and subsequent death in the sensitive cells. Furthermore, the ability of the LPS to complex with the polymyxin B molecules in resistant cells may be the basis of their resistance to the antibiotic.
The effects of the polypeptide antibiotic, polymyxin B, on myocardial contractility were studied in t;e isolated rat heart muscle. Five different doses of polymyxin B were tested. There were no changes in contractility with does ranging from the clinical therapeutic value to three times greater. There was an initial increase and then depression with a dose six times greater than the therapeutic dose. There was no direct competitive interaction between polymyxin B and halothane or Ca2+. This suggests that polymyxin B does not depress the myocardium in clinical doses and does not interfere with Ca2+ influx at the myocardial cell membrane.
In isolated adipocytes, polymyxin B inhibited insulin-induced glucose incorporation into lipids in a dose-dependent manner, while polymyxin E, a structurally related antibiotic, was ineffective. To approach the mechanism of this effect, the subcellular distribution of the glucose transporter Glut 4 was investigated. Adipocytes were pretreated without or with polymyxin B before insulin stimulation, subcellular fractionation was performed and Glut 4 was detected by immunodetection. Incubation of adipocytes with polymyxin B prevented the insulin-induced appearance of Glut 4 in the plasma membranes, but did not prevent their decrease from the low-density microsomal fraction. A lower purity of the plasma membrane fractions, a detergent effect of polymyxin B on the membranes or an interference of the substance with the immunodetection of the Glut 4 molecules were excluded. These results suggest that polymyxin B was interfering with the Glut 4 translocation process stimulated by insulin in adipocytes. In a similar fashion, polymyxin B inhibited the insulin-induced increase in IGF II binding to adipocytes. This resulted from a blockade of the appearance of IGF II receptors in the plasma membranes. Since low-molecular-mass GTP-binding proteins have been implicated in the regulation of vesicular trafficking, we have used [alpha-32P]GTP binding to analyze such proteins in adipocyte fractions, after SDS/PAGE and transfer to nitrocellulose. Specific and distinct subsets of GTP-binding proteins were revealed in plasma membrane and low-density microsomal fractions of control adipocytes, whether they were stimulated or not with insulin. Polymyxin B treatment of adipocytes markedly modified the profile of the low-molecular-mass GTP-binding proteins in plasma membranes, but not in low-density microsomal fractions. Our results suggest that polymyxin B was interfering with the exocytotic process of the Glut 4 and IGF II receptor-containing vesicles, perhaps at the fusion step between vesicles and plasma membranes.
Though the primary action of the cationic antibiotic polymyxin B is against the membrane of susceptible bacteria, severe morphological changes are detected in the cytoplasm. Using fluorescence microscopy and a mono-N-dansyl-polymyxin B derivative, we could demonstrate aggregations of the antibiotic with cellular material, possibly nucleic acids and/or ribosomes. These aggregations were only produced by minimum inhibitory or higher concentrations of the antibiotic as shown with Salmonella and Escherichia strains differing in their polymyxin susceptibility. The outer membrane of Salmonella typhimurium revealed characteristic blebs when treated with polymyxin B. This was investigated by the gentle methods of spray-freezing and freeze-etching. The obtained electron micrographs suggest that the polymyxin-induced blebs are projections of the outer monolayer of the outer membrane. A possible mechanism of penetration of polymyxin B through the cell envelope of gram-negative bacteria is presented.
The interaction between pancuronium, d-tubocurarine, polymyxin B, and neostigmine was studied in the rat diaphragm-phrenic nerve preparation. Polymyxin B (5 mug/ml) did not affect twitch tension alone but decreased the pancuronium ED50 from 0.8 mug/ml to 0.32 mug/ml and the d-tubocurarine ED50 from 0.25 mug/ml to 0.15 mug/ml. Neostigmine (0.2 to 10 mug/ml) antagonized pancuronium or d-tubocurarine-induced depression of twitch tension. In contrast, neostigmine (0.001 to 0.2 mug/ml) augmented polymyxin B depression. Similarly, neostigmine (0.1 mug/ml) augmented combined polymyxin B-pancuronium or polymyxin B-d-tubocurarine depression of twitch tension. The authors conclude that polymyxin B potentiates the neuromuscular blockade from pancuronium or d-tubocurarine and that neostigmine further augments this block.