Efflux of low-Mr substances from the cytoplasm of sensitive cells caused by the staphylococcin-like agent Pep 5

Sahl, Hans‐Georg; Brandis, H.

doi:10.1111/j.1574-6968.1983.tb00262.x

Cited by 62 publications

(42 citation statements)

References 5 publications

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“…The maximum pore diameter calculated from single channels was I nm, which should allow the permeation of molecules with molecular weights up to 600, such as ATP. This again correlates well with our physiological investigations, in which an efflux of ATP was observed (22 …”

Section: Discussionsupporting

confidence: 79%

“…The main active peptide has a molecular weight of 3,500; it contains eight positively charged amino acids and three residues of the thioether amino acid lanthionine (23). It has been shown to render cytoplasmic membranes of grampositive and gram-negative bacteria permeable to ions, amino acids, and ATP (17,22), thus causing a rapid breakdown of the membrane potential (19) and a complete cessation of biosynthesis (21). Energized cells were shown to be more sensitive to membrane depolarization by Pep 5 than starved cells were (19).…”

mentioning

confidence: 99%

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Mode of action of the staphylococcinlike peptide Pep 5: voltage-dependent depolarization of bacterial and artificial membranes

1988

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(19). This result, and the fact that cytoplasmic membranes of Mycoplasma cells, human lung fibroblasts, and erythrocytes could not be impaired (17), led us to assume that Pep 5 requires a membrane potential for disruption of cytoplasmic membranes. Such a requirement has been shown for the channel-forming colicins (7, 16), alamethicin (5), and the bee venom constituent melittin (15). To substantiate the potential dependence for the membranedisrupting activity of Pep 5, we investigated its influence on bacterial cells artificially energized by a valinomycin-induced potassium diffusion potential. Planar lipid membranes were used to elucidate the processes of Pep 5 action on energized membranes in detail.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Mode of action of the staphylococcinlike peptide Pep 5: voltage-dependent depolarization of bacterial and artificial membranes

1988

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“…As shown for type A lantibiotics pore formation depolarizes the cytoplasmic membrane (23). This leads to an immediate and complete cessation of biosynthetic processes such as DNA, RNA, protein, and polysaccharide synthesis (22).…”

Section: Discussionmentioning

confidence: 99%

Mode of action of the lantibiotic mersacidin: inhibition of peptidoglycan biosynthesis via a novel mechanism?

Brötz

Bierbaum

Markus

et al. 1995

Antimicrob Agents Chemother

131

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Mersacidin is an antibiotic peptide produced byThe term lantibiotics designates a group of lanthionine (and/or 3-methyllanthionine)-containing peptides with antibiotic activity against gram-positive bacteria (25). In contrast to peptide antibiotics like bacitracin or gramicidin S (10), lantibiotics are ribosomally synthesized and show unique structural properties, which arise from posttranslational modifications (for reviews, see references 3 and 9).With a molecular mass of 1,825 Da, mersacidin is the smallest lantibiotic known so far. Its propeptide template consists of 20 amino acids, 8 of which are modified to yield 4 thioether amino acids: 3 3-methyllanthionines and 1 2-aminovinyl-2-methylcysteine. This leads to the formation of four intramolecular heterocyclic rings. Additionally, the unusual amino acid ␣,␤-didehydroalanine is found. Mersacidin carries no net charge and has overall hydrophobic properties (5). It is produced by Bacillus sp. strain HIL Y-85,54728 and is active against several gram-positive bacteria such as streptococci, bacilli, and staphylococci including methicillin-resistant Staphylococcus aureus strains; enterococci are relatively insusceptible (4, 14). Although in vitro mersacidin is less active than vancomycin, teicoplanin, and daptomycin (17), its activity in vivo is at least comparable to that of vancomycin in the treatment of experimental staphylococcal infections (including those caused by methicillin-resistant S. aureus strains) in mice (4,14).In addition to its potential therapeutical value, mersacidin has been the subject of increased interest because of its position among the lantibiotics described so far, which have been classified into two groups (9). The type A lantibiotics (e.g., Pep5 and nisin) are screw-shaped, positively charged, amphipathic molecules which exert their primary bactericidal action by the formation of pores in the cytoplasmic membrane (20). The type B lantibiotics, as defined so far (e.g., duramycin and cinnamycin), possess a globular shape, carry no net charge or a negative charge, and are described as inhibitors of phospholipase A 2 or the angiotensin-converting enzyme (3). Mersacidin does not completely conform to either group because of atypical structural features (9, 11).Here, we report that it is also different regarding its mode of bactericidal activity. We show that mersacidin inhibits peptidoglycan biosynthesis, probably on the level of transglycosylation. Furthermore, we demonstrate that on the molecular level its mode of action differs from those of glycopeptide antibiotics like vancomycin or teicoplanin. This opens the possibility of using a new target for the antibiotic treatment of methicillinresistant S. aureus strains and makes mersacidin an interesting tool for the investigation of peptidoglycan biosynthesis of gram-positive bacteria. MATERIALS AND METHODSBacterial strains and growth conditions. Staphylococcus simulans 22 (formerly Staphylococcus cohnii 22; Institute for Medical Microbiology and Immunology of the University of Bonn, Bonn, ...

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“…Pep 5 adsorbs to gram-positive bacteria via ionic interaction with negatively charged cell wall polymers (teichoic, teichuronic, and lipoteichoic acids [LTA]) (25). The primary target of Pep 5 and nisin is the cytoplasmic membrane, which becomes permeable for small molecules such as K+, amino acids, and ATP (19,20,23). The concomitant breakdown of the membrane potential is the likely reason for cessation of biosynthesis.…”

mentioning

confidence: 99%

Autolytic system of Staphylococcus simulans 22: influence of cationic peptides on activity of N-acetylmuramoyl-L-alanine amidase

1987

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Pep 5 and nisin are cationic peptide antibiotics which in addition to their membrane-disruptive action induce autolysis in staphylococci. To investigate the mechanism of lysis induction, the influence of the peptides on the activity of the N-acetylmuramoyl-L-alanine amidase of Staphylococcus simulans 22 was studied. In experiments with isolated cell walls at low ionic strength, the amidase activity was stimulated by the addition of Pep 5 and nisin, as well as by polylysine, streptomycin, and mono-and divalent cations. The concentrations necessary for activation depended on the nature of the cation and rahged from 5 ,uM for poly-L-lysine (n = 17) to 150 mM for Na+ at a cell wail concentration of 100 ,ug of cell wails per ml. No effect was observed if the cell walls were devoid of polyanionic constituents. Kinetic data suggested that the amidase bound to the teichoic and teichuronic acids of the cell wall and was thereby inhibited. Cationic molecules reversed this inhibition, most likely by displacing the enzyme from the polyanions. If the concentrations of the larger peptides were high in relation to cell wall concentration, the activation turned into inhibition, presumably by interfering with the access of the enzyme to its substrate. These experiments demonstrate that the activity of the amidase is modulated by basic peptides in vitro and help to explain how Pep 5 and nisin may cause lysis of treated cells.

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Efflux of low-Mr substances from the cytoplasm of sensitive cells caused by the staphylococcin-like agent Pep 5

Cited by 62 publications

References 5 publications

Mode of action of the staphylococcinlike peptide Pep 5: voltage-dependent depolarization of bacterial and artificial membranes

Mode of action of the staphylococcinlike peptide Pep 5: voltage-dependent depolarization of bacterial and artificial membranes

Mode of action of the lantibiotic mersacidin: inhibition of peptidoglycan biosynthesis via a novel mechanism?

Autolytic system of Staphylococcus simulans 22: influence of cationic peptides on activity of N-acetylmuramoyl-L-alanine amidase

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