New Sipanmycin Analogues Generated by Combinatorial Biosynthesis and Mutasynthesis Approaches Relying on the Substrate Flexibility of Key Enzymes in the Biosynthetic Pathway

  title={New Sipanmycin Analogues Generated by Combinatorial Biosynthesis and Mutasynthesis Approaches Relying on the Substrate Flexibility of Key Enzymes in the Biosynthetic Pathway},
  author={M{\'o}nica G Malmierca and Ignacio P{\'e}rez-Victoria and Jes{\'u}s Mart{\'i}n and Fernando Reyes and Carmen M{\'e}ndez and Jos{\'e} A Salas and Carlos Olano},
  journal={Applied and Environmental Microbiology},
Combinatorial biosynthesis has proved its usefulness in generating derivatives of already known compounds with novel or improved pharmacological properties. Sipanmycins are a family of glycosylated macrolactams produced by Streptomyces sp. strain CS149, whose antiproliferative activity is dependent on the sugar moieties attached to the aglycone. In this work, we report the generation of several sipanmycin analogues with different deoxysugars, showing the high degree of flexibility exerted by… 
Natural polyenic macrolactams and polycyclic derivatives generated by transannular pericyclic reactions: optimized biogenesis challenging chemical synthesis.
The challenges that scientists face on the isolation of these unstable compounds from the cultures of the producing microorganisms, their structural characterization, biological activities, optimized biogenetic routes, as well as the skeletal rearrangements of the primary structures of the natural macrolactams derived from pericyclic reactions of the polyenic fragments are reviewed.
Polyene Macrolactams from Marine and Terrestrial Sources: Structure, Production Strategies, Biosynthesis and Bioactivities
Over the past few decades (covering 1972 to 2022), astounding progress has been made in the elucidation of structures, bioactivities and biosynthesis of polyene macrolactams (PMLs), but they have
Generation of incednine derivatives by mutasynthesis
28-Methylincednine showed similar suppressive activity of the antiapoptotic function of oncoprotein Bcl-xL to that of incednine, highlighting the applicability of the mutasynthesis approach in generation of novel β-amino acid-containing macrolactam polyketide derivatives.
Midecamycin Is Inactivated by Several Different Sugar Moieties at Its Inactivation Site
It is demonstrated that varied glycosylation modifications could cause inactivation of midecamycin, a 16-membered macrolide antibiotic used clinically and agriculturally and suggested that besides glucosylation, other glyCosylation patterns also could inactivate mide camycin , providing a new inactivation mechanism for mideCamycin resistance.


Cooperative Involvement of Glycosyltransferases in the Transfer of Amino Sugars during the Biosynthesis of the Macrolactam Sipanmycin by Streptomyces sp. Strain CS149
A biosynthetic pathway for sipanmycins and the two deoxy sugars attached is proposed and the importance of the hydroxyl group at C-10 of the macrolactam ring and the sugar moieties for cytotoxicity and antibiotic activity of sipan mycins is shown.
Engineered jadomycin analogues with altered sugar moieties revealing JadS as a substrate flexible O-glycosyltransferase
Results for the first time show that JadS, the GT in jadomycin biosynthesis, is a flexible O-GT that can utilize both l- and d- sugars as donor substrates, and tolerate structural changes at the C2, C4 and C6 positions of the sugar moiety.
Generation of New Derivatives of the Antitumor Antibiotic Mithramycin by Altering the Glycosylation Pattern through Combinatorial Biosynthesis
Using a combinatorial biosynthesis approach, nine mithramycin derivatives are generated, seven of which are new compounds, with alterations in the glycosylation pattern, which showed antitumor activity against different tumor cell lines.
Combinatorial biosynthesis and antibacterial evaluation of glycosylated derivatives of 12-membered macrolide antibiotic YC-17.
Biosynthesis Pathways for Deoxysugars in Antibiotic-Producing Actinomycetes: Isolation, Characterization and Generation of Novel Glycosylated Derivatives
  • J. Salas, C. Méndez
  • Biology, Engineering
    Journal of Molecular Microbiology and Biotechnology
  • 2005
This review analyzes how the knowledge coming out from isolation and characterization of deoxysugar biosynthesis pathways from actinomycetes is being used to produce novel glycosylated derivatives of natural products.
Engineered biosynthesis of glycosylated derivatives of narbomycin and evaluation of their antibacterial activities
New insight is provided into the functions of deoxysugar biosynthetic enzymes and structure–activity relationships of the sugar moieties attached to the macrolides and the potential of combinatorial biosynthesis for the generation of new macrolide carrying diverse sugars with increased antibacterial activities is demonstrated.
Deciphering biosynthesis of the RNA polymerase inhibitor streptolydigin and generation of glycosylated derivatives.
Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens
There is a constant need for new and improved drugs to combat infectious diseases, cancer, and other major life-threatening conditions. The recent development of genomics-guided approaches for novel
Exploring the biocombinatorial potential of benzoxazoles: generation of novel caboxamycin derivatives
The results show that the production of a wide variety of benzoxazoles could be potentially achieved by the sole expression of cbxBCDE genes (or orthologs thereof), supplying an external source of salicylate-like compounds, or with the concomitant expression of other genes capable of synthesizingSalicylates, such as cbXA or natPK.
New insights into paulomycin biosynthesis pathway in Streptomyces albus J1074 and generation of novel derivatives by combinatorial biosynthesis
The paulomycins biosynthesis pathway has been defined by inactivation of genes encoding glycosyltransferases, acyl transferases and enzymes involved in paulic acid and L-paulomyCose biosynthesis.