Duramycins B and C, two new lanthionine containing antibiotics as inhibitors of phospholipase A2. Structural revision of duramycin and cinnamycin.

Fredenhagen, Andreas; Fendrich, Gabriele; Märki, F; Märki, Walter; Gruner, J.; Raschdorf, F.; Peter, Heinrich H.

doi:10.7164/antibiotics.43.1403

Cited by 85 publications

(50 citation statements)

References 12 publications

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“…In addition, many nonlantibiotic bacteriocins, such as propionicin T1 (11), propionicin F (3), propionicin PLG-1 (29), propionicin SM1 (32), and jenseniin G (14), have been characterized from different species of Propionibacterium, an important genus of the Actinobacteria used in food fermentations. Lantibiotics were also characterized from different species of Streptomyces, such as ancovenin (22) and duramycins B and C (13). Recently, a novel lantibiotic compound, microbisporicin from the actinomycete Microbispora corallina, was also characterized (5,12), substantiating the propensity for lantibiotic production by different members of the Actinobacteria.…”

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Transcription Analysis of a Lantibiotic Gene Cluster from Bifidobacterium longum DJO10A

Lee

O’Sullivan

2011

Appl Environ Microbiol

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Bifidobacterium longum DJO10A was previously demonstrated to produce a lantibiotic, but only during growth on agar media. To evaluate the feasibility of production of this lantibiotic in broth media, a transcription analysis of the lanA gene was undertaken. Comparative microarray analysis of broth and agar cultures of B. longum DJO10A revealed that the lantibiotic production, modification, transport/peptidase, and immunity genes were significantly upregulated in agar cultures, while the two-component regulatory genes were expressed equally under both conditions. This suggested that the signal transduction regulatory system should function in broth cultures. Real-time PCR and Northern hybridization confirmed that lanA gene expression was significantly repressed in broth cultures. A crude lantibiotic preparation from an agar-grown culture was obtained, and its antimicrobial spectrum analysis revealed a broad inhibition range. Addition of this extract to broth cultures of B. longum DJO10A induced lanA gene expression in a dose-dependent fashion. Subinoculation using >10% of an induced broth culture maintained lanA expression. The expression of lanA was log-phase specific, being significantly downregulated in stationary phase. Transcription start analysis of lanA revealed a 284-bp 5 untranslated region, which was proposed to be involved in repression of transcription, while an inverted repeat structure located at bp ؊75 relative to the transcription start was strategically located to likely function as a binding site for the two-component response regulator. Understanding the transcription regulation of this lanA gene is the first step toward enabling production of this novel and potentially interesting lantibiotic in broth cultures.

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confidence: 95%

Transcription Analysis of a Lantibiotic Gene Cluster from Bifidobacterium longum DJO10A

Lee

O’Sullivan

2011

Appl Environ Microbiol

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“…Purification was achieved by chromatography using Amberlite XAD-I 180 and reversephase LiChroprep RP18 as described recently [3]. Duramycin B was dissolved in either H,OI'H,O (9: 1) or 'H,O respectively at a final concentration of 8 mM.…”

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confidence: 99%

“…Further unusual amino acid residues occur in the duramycin family such as 3-hydroxy-aspartic acid and a lysinoalanine bridge. The duramycins B and C have been isolated as inhibitors of phospholipase A, with activities in the micromolar range [3]. They show specific interaction with phosphatidylethanolamine, but not with the closely related phosphatidylcholine [4].…”

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Solution structures of the lantibiotics duramycin B and C

Zimmermann

Freund

Fredenhagen

et al. 1993

European Journal of Biochemistry

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The solution structures of the lantibiotics duramycin B in H,O/'H,O (9 : 1) and duramycin C in (2H,)acetonitrile/H,0 (1 : 1) have been determined by NMR followed by distance-geometry and restrained-molecular-mechanics calculations. The constitution and location of three thioether bridges and a lysinoalanine ring system could be established by unambiguously assigned NOE contacts between the bridging side chains. Model building based on NMR constraints resulted in a U-shaped topology of the tetracyclic 19-peptides with a turn around Pro9 and a kink along a virtual line from residues 5 to 13. This clamp-like conformation is stabilized by the thioether bridges and is additionally supported by an antiparallel P-strand-like structure of the N-termini and C-termini and the inherent amphiphilicity of duramycin-type lantibiotics. The duramycins B and C differ mainly in the relative mobilities of their rings A, C and D. Duramycin B is closely related to cinnamycin with an exchange of PhelO to leucine, whereas duramycin C differs from duramycin B by three conserved and two non-conserved amino-acid exchanges.The duramycins B and C belong to the class of heterodet polycyclic peptide antibiotics which were named lantibiotics [ l , 21. Their common structural elements are thioether rings formed by lanthionine and 3-methyl-lanthionine residues. Further unusual amino acid residues occur in the duramycin family such as 3-hydroxy-aspartic acid and a lysinoalanine bridge. The duramycins B and C have been isolated as inhibitors of phospholipase A, with activities in the micromolar range [3]. They show specific interaction with phosphatidylethanolamine, but not with the closely related phosphatidylcholine [4].Lantibiotics share a common biosynthesis pathway which involves the ribosomal synthesis of a prepeptide with a Nterminal leader sequence followed by post-translational modification and processing [5]. The modification involves enzymic dehydration of the serine and threonine residues in the C-terminal propeptide part to didehydroalanine and 2,3-didehydrobutyrine. Through stereospecific addition of the thiol group of cysteine residues to the double bonds of the Abbreviations. NOESY, nuclear Overhauser enhancement spectroscopy ; COSY, correlated spectroscopy ; DQF, double quantum filter; TOCSY, total correlation spectroscopy; HMQC, heteronuclear multiple quantum coherence; HMBC, heteronucledr multiple bond correlation; DISCO, differences and sums of COSY spectra; ROESY, rotating frame nuclear overhauser enhancement spectroscopy ; Ah,, L-alanine moiety of (2S,6R)-lanthionine and (2S,3S,6R)-methyllanthionine; D-Ala,, D-alanine moiety of (2S,6R)-lanthionine; Abu, (2S,3S)-p-methylalanine moiety of (2S,3S,6R)-methyllanthionine; Ala,, L-alanine moiety of (2S,9S)-lysinoalanine; HyAsp, (2S,3R)-3-hydroxy-aspartic acid; MD, molecular dynamics.Dedication. Dedicated to Prof. Murray Goodman on occasion of his 65th birthday.2,3-didehydroamino acid residues, the thioether bridges of lanthionine and b-methyl-lanthionine are formed. Addition of lys...

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“…Type A lantibiotics, such as nisin (22,39), epidermin (32), and Pep5 (28), usually act by forming pores in the cytoplasmic membrane of sensitive target organisms in processes that may involve specific molecules, such as the cell wall precursor lipid II (6,43). In contrast, type B lantibiotics, such as cinnamycin (14) and mersacidin (10), inhibit particular enzyme functions. On the basis of its leader peptide sequence, sublancin 168 was previously classified as a type A lantibiotic (30).…”

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The Large Mechanosensitive Channel MscL Determines Bacterial Susceptibility to the Bacteriocin Sublancin 168

Kouwen

Trip

Denham

et al. 2009

Antimicrob Agents Chemother

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Bacillus subtilis strain 168 produces the extremely stable and broad-spectrum lantibiotic sublancin 168. Known sublancin 168-susceptible organisms include important pathogens, such as Staphylococcus aureus. Nevertheless, since its discovery, the mode of action of sublancin 168 has remained elusive. The present studies were, therefore, aimed at the identification of cellular determinants for bacterial susceptibility toward sublancin 168. Growth inhibition and competition assays on plates and in liquid cultures revealed that sublancin 168-mediated growth inhibition of susceptible B. subtilis and S. aureus cells is affected by the NaCl concentration in the growth medium. Added NaCl did not influence the production, activity, or stability of sublancin 168 but, instead, lowered the susceptibility of sensitive cells toward this lantibiotic. Importantly, the susceptibility of B. subtilis and S. aureus cells toward sublancin 168 was shown to depend on the presence of the large mechanosensitive channel of conductance MscL. In contrast, MscL was not involved in susceptibility toward the bacteriocin nisin or Pep5. Taken together, our unprecedented results demonstrate that MscL is a critical and specific determinant in bacterial sublancin 168 susceptibility that may serve either as a direct target for this lantibiotic or as a gate of entry to the cytoplasm.

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Duramycins B and C, two new lanthionine containing antibiotics as inhibitors of phospholipase A2. Structural revision of duramycin and cinnamycin.

Cited by 85 publications

References 12 publications

Transcription Analysis of a Lantibiotic Gene Cluster from Bifidobacterium longum DJO10A

Transcription Analysis of a Lantibiotic Gene Cluster from Bifidobacterium longum DJO10A

Solution structures of the lantibiotics duramycin B and C

The Large Mechanosensitive Channel MscL Determines Bacterial Susceptibility to the Bacteriocin Sublancin 168

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