Site of action of Polymyxin on Pseudomonas aeruginosa: Antagonism by Cations

Newton, B.A.

doi:10.1099/00221287-10-3-491

Cited by 131 publications

(52 citation statements)

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“…The antibiotic activity of polymyxin B can be counteracted by high concentrations of various cations in the growth medium which presumably compete with this drug for phospholipid-binding sites (13 Additional support for the hypothesis that derepression is linked to membrane interactions can be derived from experiments with the erg-i mutant of N. crassa. As mentioned above, 30,ug of polymyxin B per ml was more inhibitory toward this strain, leading to a serious impairment of growth.…”

Section: Resultsmentioning

confidence: 68%

Antibiotic-induced derepression of the NAD-specific glutamate dehydrogenase of Neurospora crassa

Vierula

Kapoor

1987

J Bacteriol

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The catabolic, NAD-specific glutamate dehydrogenase (NAD-GDH) of Neurospora crassa is under carbon catabolite repression. Cells grown on a glycolytic carbon source, such as sucrose, have low basal levels of enzyme activity. Treatment of repressed cells with either polymyxin B or amphotericin B resulted in derepression of NAD-GDH. Derepression at the transcriptional level occurred very rapidly (within 30 min) in response to polymyxin B addition but reached a plateau within 2 h. Amphotericin B-induced derepression initiated more slowly but continued for at least 6 h, resulting in a specific activity comparable to that seen with cells transferred to glutamate as the sole carbon source. These antibiotics had no significant effect upon the activities of two constitutive enzymes, pyruvate kinase and malate dehydrogenase. Curiously, only polymyxin B treatment derepressed invertase, another catabolite-repressed enzyme. The addition of 100 mM KCI to the growth medium blocked derepression by both antibiotics, but the addition of 50 mM MgC12 only annulled derepression by polymyxin B. The ergosterol-deficient erg-i mutant, which is resistant to amphotericin B, did not derepress NAD-GDH when treated with this drug. These results are consistent with derepression resulting from interactions of these antibiotics with the plasma membrane.The filamentous fungus Neurospora crassa is well adapted for growth on a wide variety of organic substrates by virtue of a genetic capacity to synthesize a host of permeases and intra-and extracellular catabolic enzymes (11). Many of the enzymes involved in carbon acquisition are regulated by carbon catabolite repression, which enforces the preferential utilization of glucose (23). We have been studying one such enzyme, NAD-specific glutamate dehydrogenase (EC 1.4.1.2) (NAD-GDH). It is derepressed at the transcriptional level within 30 min of transfer of cells to a carbon-free medium (21). This timing of derepression is coincident with the appearance of invertase and glucomylase (23) as well as several other unidentified polypeptides which incorporate [35S]methionine. Therefore, NAD-GDH is a conveniently assayed model system for investigating the expression of catabolite-repressed genes.Although some progress has been made in the identification of mutants for putative cis-and trans-regulatory loci of catabolite repression, very little is currently known about the molecular events which mediate this control system (9, 17). The responsiveness of NAD-GDH gene expression to carbon or energy availability suggested to us that other perturbations of cellular homeostasis could simulate carbon starvation. Trevillyan and Pall (19) identified a number of agents, including the antibiotics polymyxin B and amphotericin B, which could elicit rapid disturbances of several metabolic parameters, including membrane depolarization and transient, fivefold increases in intracellular cyclic AMP (cAMP) levels.Polymyxin B is a polycationic molecule which destabilizes the cell membrane by disrupting hydrophilic and elec...

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Section: Resultsmentioning

confidence: 68%

Antibiotic-induced derepression of the NAD-specific glutamate dehydrogenase of Neurospora crassa

Vierula

Kapoor

1987

J Bacteriol

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“…The action of these antibiotics in water or in buffer is probably not related to biosynthesis of actively metabolizing bacteria. Physical surface effects, disturbing osmotic equilibrium of the cell wall, have been demonstrated for polymyxin (Few & Schulman, 1953;Newton, 1954).…”

Section: Discussionmentioning

confidence: 99%

“…Failure of streptomycin, neomycin, and polymyxin to kill some of the test bacteria rapidly in nutrient broth, although doing so in water, may be due in part to an interfering action of salts (Berkman, Henry & Housewright, 1947;Schoenhard & Stafseth, 1953;Newton, 1954). Although streptomycin and iieomycin are known to increase in activity with pH value in nutrient broth (Waksman, Bugie & Schatz, 1944;Waksman & Lechevalier, 1949), there was no correlation between pH and bactericidal action in water.…”

Section: Discussionmentioning

confidence: 99%

The Mode of Action of Antibiotic Synergism and Antagonism: the Effect in Vitro on Bacteria not Actively Multiplying

Gunnison

Kunishige

Coleman

et al. 1955

Journal of General Microbiology

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SUMMARY: The synergistic effect of certain pairs of antibiotics might be due to action on 'persisters'; i.e. members of a bacterial population which survive exposure to single drugs, perhaps while in a state of reduced metabolic activity, although their offspring do not show enhanced resistance. Hence, antibiotics were tested in vitro under conditions minimizing bacterial multiplication and metabolism. At 37", neomycin, polymyxin, and streptomycin were more effective in the absence of nutrients than in nutrient broth ; oxytetracycline and bacitracin were equally effective in either environment; but penicillin had little effect in the absence of nutrients. At 4", bactericidal action varied with the test organism so that differences could not be attributed solely to the 'resting' state of the bacteria. Conditions not permitting bacterial multiplication prevented synergism and those antagonisms demonstrable in broth. Probably synergism depends upon rapid bactericidal action preventing the emergence of persisters rather than upon destruction of these relatively inactive forms.

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“…antagonises the effect of cationic antimicrobial peptides [43,44] (this might not apply to polymyxins [45]); (4) it has been proposed that polymyxins also induce cell death through hydroxyl radical production i.e., Fenton reaction [46], and the presence of catalase in OADC would antagonise this mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro

Breda¹,

Buys²,

Apostolides³

et al. 2015

Tuberculosis

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Please cite this article in press as: van Breda SV, et al., The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro, Tuberculosis (2015), http://dx.doi.org/10.1016/j.tube.2015.05.005 SUMMARYPolymyxins have previously been described to have activity against M. tuberculosis (MTB), but further research was abandoned due to systemic toxicity concerns to achieve the required MIC. Colistin methanesulfonate (CMS), a polymyxin, is well tolerated when inhaled directly into the lungs, resulting in high local concentrations.We report here for the first time, MIC and MBC data for CMS determined by the microtiter Alamar Blue assay (MABA). We also determined how the MIC would be

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Site of action of Polymyxin on Pseudomonas aeruginosa: Antagonism by Cations

Cited by 131 publications

References 10 publications

Antibiotic-induced derepression of the NAD-specific glutamate dehydrogenase of Neurospora crassa

Antibiotic-induced derepression of the NAD-specific glutamate dehydrogenase of Neurospora crassa

The Mode of Action of Antibiotic Synergism and Antagonism: the Effect in Vitro on Bacteria not Actively Multiplying

The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro

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