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

Brötz, Heike; Bierbaum, Gabriele; Markus, A.; Molitor, Ernst; Sahl, Hans-G.

doi:10.1128/aac.39.3.714

Cited by 131 publications

(88 citation statements)

References 24 publications

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“…In the light of the new results that involve lipid II, a universal molecule in the prokaryotic world, as a target for Lcn972, it is reasonable to think of the existence of a putative cotarget that facilitates or promote access to lipid II. Lcn972 displays a very narrow inhibitory spectrum, and only On the other hand, Lcn972 is not active against nondividing cells, and electron micrographs showed that Lcn972 specifically inhibits septum formation (14) rather than promoting an overall drastic reduction of the cell wall thickness, as described for other lipid II binding lantibiotics such as mersacidin (7). These observations tentatively point to one (or more) components of the divisome as putative cotargets.…”

Section: Discussionmentioning

confidence: 53%

Specific Interaction of the Unmodified Bacteriocin Lactococcin 972 with the Cell Wall Precursor Lipid II

Martínez

Böttiger

Schneider

et al. 2008

Appl Environ Microbiol

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Lactococcin 972 (Lcn972) is a nonlantibiotic bacteriocin that inhibits septum biosynthesis in Lactococcus lactis rather than forming pores in the cytoplasmic membrane. In this study, a deeper analysis of the molecular basis of the mode of action of Lcn972 was performed. Of several lipid cell wall precursors, only lipid II antagonized Lcn972 inhibitory activity in vivo. Likewise, Lcn972 only coprecipitated with lipid II micelles. This bacteriocin inhibited the in vitro polymerization of lipid II by the recombinant S. aureus PBP2 and the addition to lipid II of the first glycine catalyzed by FemX. These experiments demonstrate that Lcn972 specifically interacts with lipid II, the substrate of both enzymes. In the presence of Lcn972, nisin pore formation was partially hindered in whole cells. However, binding of Lcn972 to lipid II could not compete with nisin in lipid II-doped 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes, possibly indicating a distinct binding site. The existence of a putative cotarget for Lcn972 activity is discussed in the context of its narrow inhibitory spectrum and the localized action at the division septum. To our knowledge, this is the first unmodified bacteriocin that binds to the cell wall precursor lipid II.

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Section: Discussionmentioning

confidence: 53%

Specific Interaction of the Unmodified Bacteriocin Lactococcin 972 with the Cell Wall Precursor Lipid II

Martínez

Böttiger

Schneider

et al. 2008

Appl Environ Microbiol

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“…The UDP-MurNAc-pentapeptide was identified by mass spectrometry. For cell wall biosynthesis assays (35), it was applied in 0.2 mM concentrations together with membranes (160 g of protein), 0.05 mM […”

Section: Methodsmentioning

confidence: 99%

Specific Binding of Nisin to the Peptidoglycan Precursor Lipid II Combines Pore Formation and Inhibition of Cell Wall Biosynthesis for Potent Antibiotic Activity

Wiedemann¹,

Breukink²,

Kraaij³

et al. 2001

Journal of Biological Chemistry

676

609

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؊1 for the wildtype peptide, and the minimum concentration for pore formation increased from the 1 nM to the 50 nM range. In contrast, peptides mutated in the flexible hinge region, e.g. [⌬N20/⌬M21]nisin, were completely inactive in the pore formation assay, but were reduced to some extent in their in vivo activity. We found the remaining in vivo activity to result from the unaltered capacity of the mutated peptide to bind to lipid II and thus to inhibit its incorporation into the peptidoglycan network. Therefore, through interaction with the membrane-bound cell wall precursor lipid II, nisin inhibits peptidoglycan synthesis and forms highly specific pores. The combination of two killing mechanisms in one molecule potentiates antibiotic activity and results in nanomolar MIC values, a strategy that may well be worth considering for the construction of novel antibiotics.The antimicrobial peptide nisin is produced by numerous strains of Lactococcus lactis and inhibits a broad range of Gram-positive bacteria (1, 2). It belongs to the lantibiotics, a group of antimicrobial peptides that is characterized by the presence of intramolecular rings formed by the thioether amino acids lanthionine and 3-methyllanthionine (3, 4). Nisin has had a long history as a potent and safe food preservative, although recent insight into the molecular mechanism of its bactericidal activity also make it interesting for biomedical applications (5, 6). Generally, the nisin-type subgroup of lantibiotics comprises elongated cationic peptides that have the capacity to adopt amphiphilic structures. Such peptides are assumed to kill microbes by disturbing the integrity of the energy-transducing membrane. Indeed, early experiments demonstrated that nisin or related lantibiotics induced rapid efflux of ions or cytoplasmic solutes such as amino acids and nucleotides. The concomitant depolarization of the cytoplasmic membrane resulted in an instant termination of all biosynthetic processes (7,8). Structural analysis in the presence of micelles indicated that the hydrophilic groups of the peptide interact with the phospholipid headgroups, and the hydrophobic side chains are immersed in the hydrophobic core of the membrane (9, 10). The wedge model as proposed by Driessen et al. (11) takes into account such structural data and proposes that the peptides insert into the membrane without losing contact with the membrane surface, resulting in the formation of a short-lived pore.Whereas the wedge model may illustrate results obtained with model membranes, a number of effects observed with intact living cells remain unexplained; in particular, the fact that nisin acts on model membranes at micromolar concentrations whereas in vivo minimal inhibitory concentration (MIC) 1 values are in the nanomolar range. The discrepancies were explained by the finding that nisin and epidermin use lipid II, the bactoprenol-bound precursor of the bacterial cell wall as a docking molecule for subsequent pore formation (12). The specificity of the nisin-lipid II interaction a...

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“…However, not all lantibiotics form pores. Mersacidin, actagardine, and cinnamycin (all members of the globular subclass II lantibiotics) only block cell wall/membrane synthesis by binding to receptors such as lipid II or phosphatidylethanolamine (23,24). Gallidermin (and related peptides) is unusual in that, while it possesses the same putative lipid II-binding motif as nisin, it is considerably shorter (22 amino acids, compared to the 34 amino acids of nisin).…”

Section: Mode Of Actionmentioning

confidence: 99%

Lantibiotic Resistance

Draper

Cotter

Hill

et al. 2015

Microbiol Mol Biol Rev

135

129

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SUMMARY The dramatic rise in the incidence of antibiotic resistance demands that new therapeutic options will have to be developed. One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine-containing peptides. It is interesting that low levels of resistance have been reported for lantibiotics compared with commercial antibiotics. Given that there are very few examples of naturally occurring lantibiotic resistance, attempts have been made to deliberately induce resistance phenotypes in order to investigate this phenomenon. Mechanisms that hinder the action of lantibiotics are often innate systems that react to the presence of any cationic peptides/proteins or ones which result from cell well damage, rather than being lantibiotic specific. Such resistance mechanisms often arise due to altered gene regulation following detection of antimicrobials/cell wall damage by sensory proteins at the membrane. This facilitates alterations to the cell wall or changes in the composition of the membrane. Other general forms of resistance include the formation of spores or biofilms, which are a common mechanistic response to many classes of antimicrobials. In rare cases, bacteria have been shown to possess specific antilantibiotic mechanisms. These are often species specific and include the nisin lytic protein nisinase and the phenomenon of immune mimicry.

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

Cited by 131 publications

References 24 publications

Specific Interaction of the Unmodified Bacteriocin Lactococcin 972 with the Cell Wall Precursor Lipid II

Specific Interaction of the Unmodified Bacteriocin Lactococcin 972 with the Cell Wall Precursor Lipid II

Specific Binding of Nisin to the Peptidoglycan Precursor Lipid II Combines Pore Formation and Inhibition of Cell Wall Biosynthesis for Potent Antibiotic Activity

Lantibiotic Resistance

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