**1. Introduction**

Although many industrial sectors have stopped their dependence on natural product (NP) drug discovery programs, NPs are still of grea<sup>t</sup> interest to many pharmaceutical communities and are important sources of bioactive compounds [1,2]. Marine microbes, as an important source of bioactive NPs, have elicited widespread attention [3–5]. However, the discovery of novel marine microbial NPs is becoming more di fficult and the rate of rediscovery of known NPs is being gradually increased. On the other hand, recent genomic sequencing has revealed the presence of numerous biosynthetic gene clusters in some microbes that may be responsible for the biosynthesis of NPs which are not found under classical cultivation conditions [6,7]. Therefore, many alternative strategies have been explored to activate these silent and cryptic biosynthetic genes. The co-culturing of marine microbes involves the culturing of two or more marine microbes together on/in certain conditions; microorganisms can communicate with each other through direct or indirect contact, thereby stimulating the silent gene clusters to produce special NPs [2,8] (Figure 1). This strategy can promote the production of complex and novel skeletons with numerous stereocenters [9–11]. Hence, the co-culturing of marine microbes draws widespread attention in the scientific community as a potential source of unknown bioactive substances classified as alkaloids, polyketides, anthraquinone, flavonoids, cyclopeptides, etc. To exploit the NPs from the co-cultures of marine microbes and understand their medicinal significance, this review summarizes successful examples involved in NPs of marine microbes based on co-cultures from 2009 to 2019 (Table 1).

**Figure 1.** The schematic diagram of novel and bioactive natural products (NPs) using co-cultures of marine fungi−fungi, fungi−bacteria and bacteria−bacteria in direct or indirect contact.


**Table 1.** Summarized NPs identified from the co-culture of marine microbes: 2009–2019.


#### **2. Compounds Derived from the Co-Cultures of Marine Microorganisms**

Co-culturing or mixed fermentation is considered an important technique of inducing secondary metabolites hidden in the genomes of marine microbes by using appropriate physiological conditions, chemical communication and competition of microbes. Consequently, it is considered an easy, cheap and effective method [12,13]. This finding also explains the chemical communication and antagonism between different marine microorganisms, such as the interactions between marine fungi−fungi, fungi−bacteria and bacteria−bacteria, in which they act as signaling molecules, competitors or defense agents [14]. Herein, the metabolites based on co-cultures of marine microbes were classified according to their skeletons as alkaloids, anthraquinones, cyclopeptides, flavonoids, macrolides, phenylpropanoids, polyketides, steroids, terpenoids and others from 2009–2019. These excellent examples were found from SciFinder, Science Direct, PubMed, Springer and other databases. Among them, the interactions between marine fungi and bacteria were found to induce the most metabolites (Figure 2A), and the alkaloids played a significant role in co-cultures of marine microbes (Figure 2B), no matter whether the mixed cultivation was of marine fungi−fungi (Figure 2C), fungi−bacteria (Figure 2D) or bacteria−bacteria (Figure 2E).

**Figure 2.** Numbers and the percentage of (**A**) isolates from the co-cultures of different marine microbes; (**B**) different classes of NPs from the co-cultures of marine microbes. The classes, numbers and proportions of NPs isolated from the co-cultures of marine (**C**) fungi and fungi, (**D**) fungi and bacteria, (**E**) bacteria and bacteria.
