microorganisms Review Recent Advances in Strategies for Activation and Discovery/Characterization of Cryptic Biosynthetic Gene Clusters in Streptomyces Chung Thanh Nguyen 1, † , Dipesh Dhakal 1, † , Van Thuy Thi Pham 1 , Hue Thi Nguyen 1 and Jae-Kyung Sohng 1,2, * 1 Department of Life Science and Biochemical Engineering, Sun Moon University, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si, Chungnam 31460, Korea; chungnguyenbio@gmail.com (C.T.N.); medipesh@gmail.com (D.D.); phamtthuyvan@gmail.com (V.T.T.P.); huenguyencute@gmail.com (H.T.N.) 2 Department of Pharmaceutical Engineering and Biotechnology, Sun Moon University, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si, Chungnam 31460, Korea * Correspondence: sohng@sunmoon.ac.kr; Tel.: +82-41-530-2246 † These authors contributed equally to this work. Received: 18 February 2020; Accepted: 22 April 2020; Published: 24 April 2020   Abstract: Streptomyces spp. are prolific sources of valuable natural products (NPs) that are of great interest in pharmaceutical industries such as antibiotics, anticancer chemotherapeutics, immunosuppressants, etc. Approximately two-thirds of all known antibiotics are produced by actinomycetes, most predominantly by Streptomyces. Nevertheless, in recent years, the chances of the discovery of novel and bioactive compounds from Streptomyces have significantly declined. The major hindrance for obtaining such bioactive compounds from Streptomyces is that most of the compounds are not produced in significant titers, or the biosynthetic gene clusters (BGCs) are cryptic. The rapid development of genome sequencing has provided access to a tremendous number of NP-BGCs embedded in the microbial genomes. In addition, the studies of metabolomics provide a portfolio of entire metabolites produced from the strain of interest. Therefore, through the integrated approaches of different-omics techniques, the connection between gene expression and metabolism can be established. Hence, in this review we summarized recent advancements in strategies for activating cryptic BGCs in Streptomyces by utilizing diverse state-of-the-art techniques. Keywords: Streptomyces; natural product; biosynthetic gene cluster; cryptic; activation 1. Introduction Natural products (NPs) derived from microbes generally possess diverse ecological and environmental impacts such as altering phenotypes, fitness, and community composition of microbes in the context of the environmental factors or ecological settings [1]. Nevertheless, in the context of human welfare, these NPs have been proven to be wonder molecules with diverse biological activities, such as antibacterials, anticancer agents, antihelminths, antidiabetics, anticholesterols, immunosuppressants, etc. Thus, they are important lead targets in the field of drug discovery and development [2,3]. Approximately 80% of anticancer agents and roughly 50% of all Food and Drug Administration-approved drugs are derived from such NPs [4]. Among all microorganisms, the actinomycetes are a prolific source of such valuable compounds that are of great interest to medicine, agriculture, and industry [5,6]. Approximately two-thirds of all known antibiotics are able to be produced by actinomycetes, most predominantly by Streptomyces [7]. Similarly, various species of Streptomyces, have been characterized as major producers of anticancer drugs [8]. In addition, Microorganisms 2020, 8, 616; doi:10.3390/microorganisms8040616 www.mdpi.com/journal/microorganisms