Complete Characterization of the Seventeen Step Moenomycin Biosynthetic Pathway (original) (raw)
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Biological Chemistry, 2000
Moenomycins are phosphoglycolipid antibiotics and the only known natural product inhibitors of peptidoglycan glycosytransferases (PGTs). Techniques that would allow facile diversification of the moenomycin structure would facilitate the development of novel antibiotics, which are urgently needed in the wake of multidrug resistant bacterial infections. The cloning and initial characterization of the moenomycin biosynthetic genes has already redefined the minimal moenomycin pharmacophore and now opens the door for the biocombinatorial generation of bioactive moenomycin fragments. Here, we highlight the importance of research on the genetic mechanisms that regulate moenomycin biosynthesis and that confer moenomycin resistance to bacteria in the development of novel anti-infectives based on PGT inhibition.
ACS Chemical Biology, 2008
eptidoglycan glycosyltransferases (PGTs) are highly conserved bacterial enzymes that catalyze the polymerization of the NAG-NAM disaccharide subunit of bacterial peptidoglycan (Figure 1) (1-5). These enzymes are regarded as attractive antibiotic targets because their structures are conserved, their functions are essential, they have no eukaryotic counterparts, and they are located on the external surface of the bacterial membrane where they are readily accessible to inhibitors (6-8). While there are not yet any antibiotics in clinical use that directly target these enzymes, the phosphoglycolipid natural product moenomycin (1, Figure 2) inhibits them at nanomolar concentrations and has potent antibiotic activity, with minimum inhibitory concentrations (MICs) 10Ϫ1000 times lower than vancomycin's MICs against various Grampositive microorganisms (6, 9). Although moenomycin is a potential lead, its therapeutic utility is limited by poor pharmacokinetic properties, including a long halflife and minimal oral bioavailability (9). In addition, although moenomycin strongly inhibits Gram-negative PGTs, its spectrum is restricted to Gram-positive microorganisms, apparently because it cannot penetrate the outer membrane of Gram-negative bacteria (10). It may be possible to overcome moenomycin's limitations by altering its structure, and the recent completion of the total synthesis of moenomycin (11-13), combined with the identification of the biosynthetic genes for its production (14), make wide-ranging explorations of structural changes feasible for the first time. Nevertheless, the complexity of moenomycin is sufficiently daunting that detailed information on how it interacts with its PGT
Moenomycin family antibiotics: chemical synthesis, biosynthesis, and biological activity
Natural Product Reports, 2010
The review (with 214 references cited) is devoted to moenomycins, the only known group of antibiotics that directly inhibit bacterial peptidoglycan glycosytransferases. Naturally occurring moenomycins and chemical and biological approaches to their derivatives are described. The biological properties of moenomycins and plausible mechanisms of bacterial resistance to them are also covered here, portraying a complete picture of the chemistry and biology of these fascinating natural products
Russian Journal of Genetics, 2014
Moenomycins (Mm)-phosphoglycolipid compounds produced by Streptomyces ghanaensis ATCC14672-are considered a promising model for development of novel class of antibiotics. In this regard it is important to generate Mm overproducing strains which would be a basis for economically justified pro duction of this antibiotic. In this work a set of genes for synthesis and reception of low molecular weight sig naling molecules (LSM) in ATCC14672 were described and their significance for Mm production was stud ied. The ATCC14672 genome carries structural and regulatory genes for production of LSMs of avenolide and γ butyrolactone families. Additional copies of LSM biosynthetic genes ssfg_07848 and ssfg_07725 did not alter the Mm production level. ATCC14672 LSMs are not capable of restoring the sporulation of butyro lactone nonproducing mutant of S. griseus. Likewise, while the heterologous host S. lividans 1326 produced Mm, its mutant M707 (deficient in the butyrolactone synthase gene scbA) did not. Thus, while the natural level of LSMs production by ATCC14672 does not limit Mm synthesis, the former is essential for the synthe sis of moenomycins.
Tetrahedron, 1997
Moenomycin A (18) on reaction with the diazonium salt derived from bifmtctional (protected) 15 yields the coupling product 19 which on reduction is converted into the moenomycin thiol derivative 21. Thiol21 has been used to prepare selectively moenomycin dansyl and biotin adducts 26 and 28, respectively. This work was performed with the aim to use moenomycin as a tool for studies of the transglycosylation step in peptidoglycan biosynthesis. 0 1997 Elsevier Science Ltd.
Genetic factors that influence moenomycin production in streptomycetes
Journal of Industrial Microbiology & Biotechnology, 2010
Moenomycin, a natural phosphoglycolipid product that has a long history of use in animal nutrition, is currently considered an attractive starting point for the development of novel antibiotics. We recently reconstituted the biosynthesis of this natural product in a heterologous host, Streptomyces lividans TK24, but production levels were too low to be useful. We have examined several other streptomycetes strains as hosts and have also explored the overexpression of two pleiotropic regulatory genes, afsS and relA, on moenomycin production. A moenomycin-resistant derivative of S. albus J1074 was found to give the highest titers of moenomycin, and production was improved by overexpressing relA. Partial duplication of the moe cluster 1 in S. ghanaensis also increased average moenomycin production. The results reported here suggest that rational manipulation of global regulators combined with increased moe gene dosage could be a useful technique for improvement of moenomycin biosynthesis.
Tetrahedron, 2011
We present a flexible, modular route to GlcNAc-MurNAc-oligosaccharides that can be readily converted into peptidoglycan (PG) fragments to serve as reagents for the study of bacterial enzymes that are targets for antibiotics. Demonstrating the utility of these synthetic PG substrates, we show that the tetrasaccharide substrate lipid IV (3), but not the disaccharide substrate lipid II (2), significantly increases the concentration of moenomycin A required to inhibit a prototypical PG-glycosyltransferase (PGT). These results imply that lipid IV and moenomycin A bind to the same site on the enzyme. We also show the moenomycin A inhibits the formation of elongated polysaccharide product but does not affect length distribution. We conclude that moenomycin A blocks PG-strand initiation rather than elongation or chain termination. Synthetic access to diphospholipid oligosaccharides will enable further studies of bacterial cell wall synthesis with the long-term goal of identifying novel antibiotics.
2017
The genus Streptomyces is known to be responsible for the production of more than two-thirds of the world’s antibiotics, through complex specialised metabolic pathways. However, given the high frequency of rediscovery of known antibiotics and the challenge of producing novel analogues via chemical synthesis, biosynthetic engineering has emerged as an attractive approach to optimising antibiotic natural products for clinical use. This technique utilises enzymes from antibiotic biosynthetic pathways to create novel antibiotic derivatives. However, its application requires an understanding of how antibiotics are biosynthesised. This work is focused on the methylenomycin antibiotics produced by Streptomyces coelicolor A 3 (2), a model Actinobacterium. The cluster of genes directing methylenomycin production and its regulation are carried on the giant linear plasmid SCP1. The sequencing of the entire 356-kb SCP1 plasmid allowed bioinformatics analyses to be applied to the assignment of p...