Optimizing Nystatin Biosynthesis Through Targeted Manipulation of nysL and nysGtf in Streptomyces noursei
6 affiliations
- 1School of Life Sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
- 2School of Functional Food and Wine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
- 3School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
- 4Beijing Global Biologicals Inc., 99 Yuexiu Road, Beijing 100192, China
- 5Care4living Oy, Itäinen Pitkäkatu 4, 20520 Turku, Finland
- 6Department of Life Technologies, University of Turku, Tykistökatu 6, 20520 Turku, Finland
Abstract
Nystatin, a polyene macrolide antifungal agent produced by Streptomyces noursei, exists as three major derivatives (nystatin A1, A3, polyfungin B) with distinct C-10 and C-35 modifications. Although the core catalytic functions of NysL and NysGtf have been established, the metabolic crosstalk between the C-10 hydroxylation and C-35 digitosylation branches, together with the in vivo substrate promiscuity of NysGtf in industrial S. noursei, remains poorly understood. In this study, we constructed gene-disruption, complementation and overexpression mutants of S. noursei 72-22-1 to characterize nysL and nysGtf. While NysL has previously been established as the C-10 hydroxylase, we characterized its role in the industrial derivative strain 72-22-1. nysL disruption abolished C-10 hydroxylation, eliminated nystatin A1/A3 and caused accumulation of 10-deoxynystatin and polyfungin B, while complementation and/or overexpression restored A1/A3 formation. nysGtf inactivation blocked C-35 glycosylation, raising nystatin A1 titer to 0.587 mg/mL and decreasing polyfungin B to 0.027 mg/mL. Its overexpression enhanced nystatin A3 production to 1.195 mg/mL. Our findings define the physiological roles of NysL and NysGtf in nystatin biosynthesis, identify polyfungin B as the key antifungal component, and provide a feasible strategy for metabolic engineering of S. noursei to generate high-activity nystatin derivatives.
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BibTeX
@article{shi2026optimizing,
title = {{Optimizing Nystatin Biosynthesis Through Targeted Manipulation of nysL and nysGtf in Streptomyces noursei}},
author = {Jibin Shi and Dexi Song and Junran Yang and Xianpu Ni and Yitong Xu and Fuju Wang and Kristiina Ylihonko and Mikko Metsä-Ketelä and Ming Song and Weizhuo Xu},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219572},
url = {https://www.mdpi.com/1422-0067/27/21/9572},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Optimizing Nystatin Biosynthesis Through Targeted Manipulation of nysL and nysGtf in Streptomyces noursei
AU - Jibin Shi
AU - Dexi Song
AU - Junran Yang
AU - Xianpu Ni
AU - Yitong Xu
AU - Fuju Wang
AU - Kristiina Ylihonko
AU - Mikko Metsä-Ketelä
AU - Ming Song
AU - Weizhuo Xu
PY - 2026
DA - 2026/10/26
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219572
UR - https://www.mdpi.com/1422-0067/27/21/9572
AB - Nystatin, a polyene macrolide antifungal agent produced by Streptomyces noursei, exists as three major derivatives (nystatin A1, A3, polyfungin B) with distinct C-10 and C-35 modifications. Although the core catalytic functions of NysL and NysGtf have been established, the metabolic crosstalk between the C-10 hydroxylation and C-35 digitosylation branches, together with the in vivo substrate promiscuity of NysGtf in industrial S. noursei, remains poorly understood. In this study, we constructed gene-disruption, complementation and overexpression mutants of S. noursei 72-22-1 to characterize nysL and nysGtf. While NysL has previously been established as the C-10 hydroxylase, we characterized its role in the industrial derivative strain 72-22-1. nysL disruption abolished C-10 hydroxylation, eliminated nystatin A1/A3 and caused accumulation of 10-deoxynystatin and polyfungin B, while complementation and/or overexpression restored A1/A3 formation. nysGtf inactivation blocked C-35 glycosylation, raising nystatin A1 titer to 0.587 mg/mL and decreasing polyfungin B to 0.027 mg/mL. Its overexpression enhanced nystatin A3 production to 1.195 mg/mL. Our findings define the physiological roles of NysL and NysGtf in nystatin biosynthesis, identify polyfungin B as the key antifungal component, and provide a feasible strategy for metabolic engineering of S. noursei to generate high-activity nystatin derivatives.
SN - 1422-0067
ER -