*Review* **The Structural Diversity of Marine Microbial Secondary Metabolites Based on Co-Culture Strategy: 2009–2019**

#### **Jianwei Chen 1, Panqiao Zhang 1, Xinyi Ye 1, Bin Wei 1, Mahmoud Emam 1,2, Huawei Zhang 1 and Hong Wang 1,\***

1 College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; cjw983617@zjut.edu.cn (J.C.); 18668358826@163.com (P.Z.); xinyiye1020@zjut.edu.cn (X.Y.); binwei@zjut.edu.cn (B.W.); mahmoudemamhegazy2020@gmail.com(M.E.);hwzhang@zjut.edu.cn(H.Z.)


Received: 28 July 2020; Accepted: 25 August 2020; Published: 27 August 2020

**Abstract:** Marine microorganisms have drawn grea<sup>t</sup> attention as novel bioactive natural product sources, particularly in the drug discovery area. Using di fferent strategies, marine microbes have the ability to produce a wide variety of molecules. One of these strategies is the co-culturing of marine microbes; if two or more microorganisms are aseptically cultured together in a solid or liquid medium in a certain environment, their competition or synergetic relationship can activate the silent biosynthetic genes to produce cryptic natural products which do not exist in monocultures of the partner microbes. In recent years, the co-cultivation strategy of marine microbes has made more novel natural products with various biological activities. This review focuses on the significant and excellent examples covering sources, types, structures and bioactivities of secondary metabolites based on co-cultures of marine-derived microorganisms from 2009 to 2019. A detailed discussion on future prospects and current challenges in the field of co-culture is also provided on behalf of the authors' own views of development tendencies.

**Keywords:** co-culture; marine microbes; natural products; structural diversity; biological activities
