Fan Zhang

University of Wisconsin–Madison

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Kenneth J. Barns

University of Wisconsin–Madison

Liwei Yi

Central South University

Miao Zhao

Liaoning University of Traditional Chinese Medicine

Cameron R. Currie

McMaster University

Tim S. Bugni

University of Wisconsin–Madison

Yanwen Duan

Central South University

Yong Huang

Sichuan Agricultural University

Marc G. Chevrette

University of Florida

Gene E. Ananiev

University of Wisconsin Carbone Cancer Center

Xiangcheng Zhu

University of California, Los Angeles

Cooperative Institutions

University of Wisconsin–Madison

Central South University

University of Wisconsin Carbone Cancer Center

Fudan University Shanghai Cancer Center

Shanghai Medical College of Fudan University

Great Lakes Bioenergy Research Center

Madison Group (United States)

Shanghai Cancer Institute

Cancer Institute (WIA)

Wisconsin Institutes for Discovery

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The antimicrobial potential of Streptomyces from insect microbiomes

Nature Communications (2019)

Marc G. Chevrette Caitlin M. Carlson Humberto E. Ortega Chris S. Thomas Gene E. Ananiev

Abstract Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. Natural products, particularly from Streptomyces , are the source of most antimicrobials, yet discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds. Investigation of understudied and symbiotic sources has seen some success, yet no studies have systematically explored microbiomes for antimicrobials. Here we assess the distinct evolutionary lineages of Streptomyces from insect microbiomes as a source of new antimicrobials through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models. Insect-associated Streptomyces inhibit antimicrobial-resistant pathogens more than soil Streptomyces . Genomics and metabolomics reveal their diverse biosynthetic capabilities. Further, we describe cyphomycin, a new molecule active against multidrug resistant fungal pathogens. The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens, supporting the promise of this source in augmenting future antimicrobial discovery.

10.1038/s41467-019-08438-0

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Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization

National Science Review (2021)

Jintao Li Kai-Yue Li Ying Su Shen Yuan Mingzhu Lei

BCAT2-mediated branched-chain amino acid (BCAA) catabolism is critical for pancreatic ductal adenocarcinoma (PDAC) development, especially at an early stage. However, whether a high-BCAA diet promotes PDAC development in vivo, and the underlying mechanism of BCAT2 upregulation, remain undefined. Here, we find that a high-BCAA diet promotes pancreatic intraepithelial neoplasia (PanIN) progression in LSL-KrasG12D/+ ; Pdx1-Cre (KC) mice. Moreover, we screened with an available deubiquitylase library which contains 31 members of USP family and identified that USP1 deubiquitylates BCAT2 at the K229 site. Furthermore, BCAA increases USP1 protein at the translational level via the GCN2-eIF2α pathway both in vitro and in vivo. More importantly, USP1 inhibition recedes cell proliferation and clone formation in PDAC cells and attenuates pancreas tumor growth in an orthotopic transplanted mice model. Consistently, a positive correlation between USP1 and BCAT2 is found in KC; LSL-KrasG12D/+ ; p53flox/+ ; Pdx1-Cre mice and clinical samples. Thus, a therapeutic targeting USP1-BCAT2-BCAA metabolic axis could be considered as a rational strategy for treatment of PDAC and precisive dietary intervention of BCAA has potentially translational significance.

Catabolism

PDX1

10.1093/nsr/nwab212

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Discovery of gas vesicles in Streptomyces sp. CB03234-S and potential effects of gas vesicle gene overexpression on morphological and metabolic changes in streptomycetes

Applied Microbiology and Biotechnology (2019)

Rong Huang Jin Lin Die Gao Fan Zhang Liwei Yi

Gene cluster

Streptomycetaceae

10.1007/s00253-019-09891-z

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A marine microbiome antifungal targets urgent-threat drug-resistant fungi

Science (2020)

Fan Zhang Miao Zhao Doug R. Braun Spencer S. Ericksen Jeff S. Piotrowski

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.

Candida auris

Mode of Action

Antifungal drugs

10.1126/science.abd6919

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Streptomycin‐induced ribosome engineering complemented with fermentation optimization for enhanced production of 10‐membered enediynes tiancimycin‐A and tiancimycin‐D

Biotechnology and Bioengineering (2019)

Zhoukang Zhuang Chengzhou Jiang Fan Zhang Rong Huang Liwei Yi

Abstract Tiancimycins (TNMs) are a group of 10‐membered anthraquinone‐fused enediynes, newly discovered from Streptomyces sp. CB03234. Among them, TNM‐A and TNM‐D have exhibited excellent antitumor performances and could be exploited as very promising warheads for the development of anticancer antibody‐drug conjugates (ADCs). However, their low titers, especially TNM‐D, have severely limited following progress. Therefore, the streptomycin‐induced ribosome engineering was adopted in this work for strain improvement of CB03234, and a TNMs high producer S . sp. CB03234‐S with the K43N mutation at 30S ribosomal protein S12 was successfully screened out. Subsequent media optimization revealed the essential effects of iodide and copper ion on the production of TNMs, while the substitution of nitrogen source could evidently promote the accumulation of TNM‐D, and the ratio of produced TNM‐A and TNM‐D was responsive to the change of carbon and nitrogen ratio in the medium. Further amelioration of the pH control in scaled up 25 L fermentation increased the average titers of TNM‐A and TNM‐D up to 13.7 ± 0.3 and 19.2 ± 0.4 mg/L, respectively. The achieved over 45‐fold titer improvement of TNM‐A, and 109‐fold total titer improvement of TNM‐A and TNM‐D enabled the efficient purification of over 200 mg of each target molecule from 25 L fermentation. Our efforts have demonstrated a practical strategy for titer improvement of anthraquinone‐fused enediynes and set up a solid base for the pilot scale production and preclinical studies of TNMs to expedite the future development of anticancer ADC drugs.

Industrial fermentation

10.1002/bit.26944

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Citations (32)