Determining the Structure and Mode of Action of Microbisporicin, a Potent Lantibiotic Active Against Multiresistant Pathogens

Castiglione, Francesca; Lazzarini, Ameriga; Carrano, Lùcia; Corti, Emiliana; Ciciliato, Ismaela; Gastaldo, Luciano; Candiani, Paolo; Losi, Daniele; Marinelli, Flavia; Selva, Enrico; Parenti, Francesco

doi:10.1016/j.chembiol.2007.11.009

Cited by 185 publications

(170 citation statements)

References 35 publications

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“…2B). Moreover, microbisporicin has a similar N-terminal structure to that of nisin, but is produced by Actinobacteria (22,23), and its LanC does not even belong to group 3, which harbors most enzymes for nisin-like lanthipeptides. These results demonstrate convergent evolution to arrive at nisin-like architectures.…”

Section: Resultsmentioning

confidence: 99%

Evolution of lanthipeptide synthetases

Zhang

Velásquez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

173

244

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Lanthionine-containing peptides (lanthipeptides) are a family of ribosomally synthesized and posttranslationally modified peptides containing (methyl)lanthionine residues. Here we present a phylogenomic study of the four currently known classes of lanthipeptide synthetases (LanB and LanC for class I, LanM for class II, LanKC for class III, and LanL for class IV). Although they possess very similar cyclase domains, class II-IV synthetases have evolved independently, and LanB and LanC enzymes appear to not always have coevolved. LanM enzymes from various phyla that have three cysteines ligated to a zinc ion (as opposed to the more common CysCys-His ligand set) cluster together. Most importantly, the phylogenomic data suggest that for some scaffolds, the ring topology of the final lanthipeptides may be determined in part by the sequence of the precursor peptides and not just by the biosynthetic enzymes. This notion was supported by studies with two chimeric peptides, suggesting that the nisin and prochlorosin biosynthetic enzymes can produce the correct ring topologies of epilancin 15X and lacticin 481, respectively. These results highlight the potential of lanthipeptide synthetases for bioengineering and combinatorial biosynthesis. Our study also demonstrates unexplored areas of sequence space that may be fruitful for genome mining. molecular evolution | natural products | phylogeny | posttranslational modification | lantibiotics

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Section: Resultsmentioning

confidence: 99%

Evolution of lanthipeptide synthetases

Zhang

Velásquez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

173

244

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“…Among the Antibiotic discovery in the twenty-first century S Donadio et al new lantibiotics identified, the most active compound was NAI-107 (Figure 2a), produced by Microbispora sp. 39 This compound represents the first example of a class I lantibiotic produced by actinomycetes. It is currently a developmental candidate for the treatment of nosocomial infections by Gram-positive pathogens.…”

Section: Improved Variants From Microbial Sourcesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

223

126

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New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

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“…pIJ12321 was PCR targeted to introduce an integrase (int⌽C31), phage attachment site (attP), origin of transfer (oriT), and apramycin resistance cassette [aac(3)IV], creating pIJ12323. (3) and microbisporicin (4). Residues are unmodified (white), dehydrated (purple), dehydrated and cyclized (blue), or modified in other ways (green).…”

Section: Methodsmentioning

confidence: 99%

“…1B) (3) and suggested that planosporicin was indeed ribosomally synthesized. Evidence thus far indicates that planosporicin inhibits cell wall biosynthesis (22), and its N-terminal similarity to nisin (23) and microbisporicin (4) suggests an ability to bind to lipid II, the immediate precursor for cell wall biosynthesis (24). Planomonospora is a genus in the family Streptosporangiaceae with a high genomic GC content that forms a highly differentiated, branched mycelium that sporulates to form clavate monospores (25).…”

mentioning

confidence: 99%

Cloning and Analysis of the Planosporicin Lantibiotic Biosynthetic Gene Cluster of Planomonospora alba

2013

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The increasing prevalence of antibiotic resistance in bacterial pathogens has renewed focus on natural products with antimicrobial properties. Lantibiotics are ribosomally synthesized peptide antibiotics that are posttranslationally modified to introduce (methyl)lanthionine bridges. Actinomycetes are renowned for their ability to produce a large variety of antibiotics, many with clinical applications, but are known to make only a few lantibiotics. One such compound is planosporicin produced by Planomonospora alba, which inhibits cell wall biosynthesis in Gram-positive pathogens. Planosporicin is a type AI lantibiotic structurally similar to those which bind lipid II, the immediate precursor for cell wall biosynthesis. The gene cluster responsible for planosporicin biosynthesis was identified by genome mining and subsequently isolated from a P. alba cosmid library. A minimal cluster of 15 genes sufficient for planosporicin production was defined by heterologous expression in Nonomuraea sp. strain ATCC 39727, while deletion of the gene encoding the precursor peptide from P. alba, which abolished planosporicin production, was also used to confirm the identity of the gene cluster. Deletion of genes encoding likely biosynthetic enzymes identified through bioinformatic analysis revealed that they, too, are essential for planosporicin production in the native host. Reverse transcription-PCR (RT-PCR) analysis indicated that the planosporicin gene cluster is transcribed in three operons. Expression of one of these, pspEF, which encodes an ABC transporter, in Streptomyces coelicolor A3(2) conferred some degree of planosporicin resistance on the heterologous host. The inability to delete these genes from P. alba suggests that they play an essential role in immunity in the natural producer.

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Determining the Structure and Mode of Action of Microbisporicin, a Potent Lantibiotic Active Against Multiresistant Pathogens

Cited by 185 publications

References 35 publications

Evolution of lanthipeptide synthetases

Evolution of lanthipeptide synthetases

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Cloning and Analysis of the Planosporicin Lantibiotic Biosynthetic Gene Cluster of Planomonospora alba

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