Combinatorial Biosynthesis of Cyclic Lipopeptide Antibiotics: A Model for Synthetic Biology To Accelerate the Evolution of Secondary Metabolite Biosynthetic Pathways

Baltz, Richard H.

doi:10.1021/sb3000673

Cited by 125 publications

(119 citation statements)

References 71 publications

(208 reference statements)

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“…Daptomycin and all other members of the A21978C group of lipopeptides are synthesized by the same modular non-ribosomal synthetase system 22 (see Figure 2) and contain the same peptide moiety; the only part of the structure that differs between them is the N-terminally attached fatty acyl residue. The common peptide moiety contains 13 amino acids, six of which are non-proteinogenic: D-Asn (2) , ornithine (Orn (6) ), D-Ala (8) , D-Ser (11) , (2S,3R)-methylglutamate (MeGlu (12) ), and kynurenine (Kyn (13) ).…”

Section: Structure and Biosynthesismentioning

confidence: 99%

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The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

225

172

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Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Streptomyces roseosporus that is clinically used to treat severe infections with Grampositive bacteria. In this review, we discuss the mode of action of this important antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimental studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This activity, which can account for daptomycin's bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial resistance to daptomycin. While other resistance mechanisms suggest that daptomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin's complex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space.

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Section: Structure and Biosynthesismentioning

confidence: 99%

“…Through genetic recombination of these modular synthetases, hybrid lipopeptides can be generated. 22 One such study explored a series of hybrids between daptomycin and A54145. 33 A54145 is more toxic than daptomycin, but unlike the latter is not inhibited by lung surfactant.…”

Section: Relationship To Other Calcium-dependent Lipopeptide Antibioticsmentioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

225

172

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“…48 The three subunit arrangement has also been observed in the highly related cryptic daptomycin-like pathway in the finished genome of Saccharopolyspora viridis 49 and the finished biosynthetic gene cluster for taromycin A in the marine Saccharopolyspora sp. CNQ-490.…”

Section: Assembly Of Nrps and Pks-i Mega-genes In Draft Genome Sequencesmentioning

confidence: 91%

“…The PCP-TE pentamer was constructed from the third subunit of the daptomycin NRPS cluster (DptD) and four uncharacterized NRPS subunits from Streptomyces griseus, S. avermitilis, Amycolatopsis orientalis and Streptomyces clavuligerus. The use of five diverse CP-TE di-domains in each case, coupled with the use of DELTA BLASTp, 48 gives high likelihood that individual ACP-TE and PCP-TE di-domains in finished and draft genomes will be counted as surrogates for the number of NRPS-PKS-I gene clusters, independent of poor assembly and fragmentation of large pathways into smaller erroneous SMGCs in antiSMASH 3.0 searches of draft genomes. It is instructive that the ACP-TE multi-probe readily picks up the terminal ACP-TEs of SpnE and TylGV, and the PCP-TE multi-probe picks up the terminal PCP-TE of DptD in draft genomes, even though the tylosin, spinosad and daptomycin gene clusters were assembled incorrectly ( Table 1).…”

Section: Construction Of Acp-te and Pcp-te Multi-probesmentioning

confidence: 99%

Molecular beacons to identify gifted microbes for genome mining

Baltz¹

2017

J Antibiot

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Microbial genome mining is a promising technology that is revitalizing natural product discovery. It is now well documented that many bacteria with large genomes, particularly actinomycetes, encode many more secondary metabolites (SMs) than was previously known from their expressed secondary metabolomes. There are effective bioinformatics tools for counting the numbers and nature of SMs, and determining the total coding capacity from finished microbial genomes. However, these methods do not translate well to draft genomes, particularly for large SM gene clusters that contain nonribosomal peptide synthetase (NRPS) or type I polyketide synthase (PKS-I) mega-genes which are prone to fragmentation and misassembly. Small molecular beacons are required to assess the numbers and variety of NRPS, PKS-I and mixed NRPS/PKS-I pathways. In this report, I show that concatenated peptidyl carrier protein-thioesterase di-domains and acyl carrier protein-thioesterase di-domains can be used as multi-probes to survey finished or draft genomes to estimate the numbers of NRPS, PKS-I and mixed NRPS/PKS-I gene clusters to identify gifted actinomycetes.

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“…Peptides are an important part of the antibiotic area [8,52]. They include vancomycin, teicoplanin, the streptogramins, and the bacteriocins.…”

Section: Antibioticsmentioning

confidence: 99%

Importance of microbial natural products and the need to revitalize their discovery

Demain

2014

Journal of Industrial Microbiology and Biotechnology

361

216

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Microbes are the leading producers of useful natural products. Natural products from microbes and plants make excellent drugs. Significant portions of the microbial genomes are devoted to production of these useful secondary metabolites. A single microbe can make a number of secondary metabolites, as high as 50 compounds. The most useful products include antibiotics, anticancer agents, immunosuppressants, but products for many other applications, e.g., antivirals, anthelmintics, enzyme inhibitors, nutraceuticals, polymers, surfactants, bioherbicides, and vaccines have been commercialized. Unfortunately, due to the decrease in natural product discovery efforts, drug discovery has decreased in the past 20 years. The reasons include excessive costs for clinical trials, too short a window before the products become generics, difficulty in discovery of antibiotics against resistant organisms, and short treatment times by patients for products such as antibiotics. Despite these difficulties, technology to discover new drugs has advanced, e.g., combinatorial chemistry of natural product scaffolds, discoveries in biodiversity, genome mining, and systems biology. Of great help would be government extension of the time before products become generic.

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Combinatorial Biosynthesis of Cyclic Lipopeptide Antibiotics: A Model for Synthetic Biology To Accelerate the Evolution of Secondary Metabolite Biosynthetic Pathways

Cited by 125 publications

References 71 publications

The action mechanism of daptomycin

The action mechanism of daptomycin

Molecular beacons to identify gifted microbes for genome mining

Importance of microbial natural products and the need to revitalize their discovery

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