On April 14, the team of Professor Duan Yanwen from the Xiangya International Academy of Translational Medicine at Central South University published an original article entitled “Platensimycin-encapsulated poly (lactic- co-glycolic acid) and poly (amidoamine) dendrimers nanoparticles with enhanced anti-staphylococcal activity in vivo” (doi 10.1021/acs.bioconjchem.0c00121) inBioconjugate Chemistrywith Liu Xingyun, a 2017 doctoral student, as the first author, and Professor Duan Yanwen and Researcher Huang Yong as the corresponding authors.TheBioconjugate Chemistryis a famous journal of biochemical methodology under the American Chemical Society.
Antibiotic resistance causes 700,000 deaths each year (Wellcome Trust and HM Government, London, 2016), so it is urgent to develop new antibiotics. Platensimycin (PTM), a selective inhibitor of FabB/FabF for bacterial fatty acid biosynthesis, has excellent activity against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci), and is thus considered to be an actinomycete-derived star natural product which has huge prospects of development. Duan Yanwen’s team has been working for many years to build a technical platform for high-throughput screening and developing of new anti-tumor antibiotic drugs from microbial-derived compounds. In the early stage, six platensimycin-producing high-yield strains were obtained through genome mining technology; high-yield engineering bacteria were constructed by genetically regulating their biosynthesis and fermentation optimization, and pilot-scale production of platensimycin was achieved. However, easy clearance in animals and low in vivo bioavailability hindered the clinical development of platensimycin. Therefore, this study applied nanotechnology to the development of platensimycin, used poly (lactic-co-glycolic acid) (PLGA) and poly (amidoamine) (PAMAM) dendrimer as carriers to construct PTM/PLGA nanoparticles (NPs) and PAMAM/PTM NPs. The nano-delivery system improves the effect of platensimycin against intracellular bacterial infections, and significantly improves the pharmacokinetic properties of platensimycin, and ultimately improves the survival rate of lethal peritonitis in Staphylococcus aureus infection. This study shows the great potential for the development of nanometer new-generation antimicrobial drug platensimycin.
Duan Yanwen’s team discovered a series of new enediyne natural products, including tiancimycin, through innovative genome mining technology. Tiancimycin is a new type of ten-membered anthraquinone enediyne and a nuclear molecule for the next-generation anti-tumor antibody-drug conjugates (ADCs). In the latest research progress, the team obtained the most stable tiancimycin-producing high-yield strain CB03234-GS26 through ribosomal engineering and genome shuffling. Through synthetic biological research, the yield of tiancimycin was increased by 70 times and pilot product was realized in the fermentor. Gene knockout shows that in addition to ribosome engineering, there should be other possible genomic variations and mechanisms to enhance the biosynthesis of tiancimycin. Therefore, CB03234-GS26 provides a basis for finding potential new genetic targets and exploring the interaction between complex metabolic networks and tiancimicin biosynthetic pathways, which promotes the transformation of the high-yield systems for producing tiancimicin and other anthraquinone-fused dienynes, provides a reference for the metabolic engineering transformation of other streptomyces, and accelerates the development of ADCs. The latest research result “Genome shuffling based on different types of ribosome engineering mutants for enhanced production of 10-membered enediynetiancimycin-A” was published in a well-known international applied microbiology journal Applied Microbiology and Biotechnology (doi: 10.1007/s00253-020-10583-2) with Liu Huiming, a 2017 graduate student, as the first author, and Professor Duan Yanwen and Researcher Zhu Xiangcheng as the corresponding authors.
Actinomycete-derived natural products play an important role in the discovery of new drugs, and have great potential in the discovery of new drugs in the secondary metabolites of actinomycetes. The team took an activity-oriented way to isolate a number of novel pyrroloformamide natural products from the secondary metabolites of actinomycetes, which have antibacterial and antitumor activities that target a key genetic driver of cancer, rather than a specific type of tumor. The characterization of the biosynthetic gene clusters of the natural products reveals the biosynthesis mechanisms of pyrroloformamides and dithiolopyrrolone natural products (including holomycin and thiolutin). The results were published in Journal of Natural Products, a top journal in the field of natural products, entitled “The isolation of pyrroloformamide congeners and characterization of their biosynthetic gene cluster” (83, 202-209). The first author of the article is Zhou Wenqing, a 2016 graduate student and Liang Haoyu, a 2015 PhD student, and the corresponding authors are Professor Duan Yanwen and Researcher Huang Yong.
Source: News Center