**1. Introduction**

Microbially produced natural products (NPs) are an important reservoir of therapeutic and agricultural agents [1]. In the previous years, quantities of new bioactive NPs were isolated from marine-derived *Streptomyces* strains, suggesting marine-derived *Streptomyces* as a predominant source of new NPs [2]. In recent years, whole-genome sequencing programs have made it clear that microorganisms have greater biosynthetic potential but are mostly underexplored by virtue that most biosynthetic gene clusters (BGCs) in a single microbial genome are normally silent. Activation of these silent BGCs contributes to new NPs discoveries. Zhang and co-workers activated a cryptic polycyclic tetramate macrolactam (PTM) BGC in *Streptomyces pactum* SCSIO 02999 by promoter engineering and heterologous expression [3], and also promoted the expression of a silent PKS/NRPS hybrid BGC in the same *Streptomyces* strain by the alteration of several regulatory genes [4]. The production of nocardamine [5] and atratumycin [6] in *Streptomyces atratus* SCSIO ZH16 was turned on via metabolic engineering. These genome-based studies exemplify the benefits of genome mining and metabolic engineering used for activating cryptic BGCs and discovering new bioactive NPs.

Lobophorins (Supporting Information (SI), Figure S1) belonging to a large class of spirotetronate antibiotics structurally feature a tetronate moiety *spiro*-linked with a cyclohexene ring, which is called pentacyclic aglycon or kijanolide [7–17]. Almost all of this class of compounds has a broad spectrum of antibacterial activities, as well as antitumor activity. Efforts to produce more spirotetronate antibiotics for drug discovery have thrived. Owing to the structural complexity of this family member, biosynthesis seems to be an effective way to afford the production of spirotetronate antibiotics, providing access to new analogues by pathway engineering and combinatorial biosynthetic approaches. In this paper, we report (i) the complete genome sequence of a deep-sea-derived *Streptomyces olivaceus* SCSIO T05, a talented strain capable of producing an array of putative NPs; (ii) activation of a cryptic lobophorin BGC (*lbp*) by mutagenetic methods and isolation of one known spirotetronate antibiotic lobophorin CR4 (**1**); and (iii) identification of the *lbp* BGC housed in *S. olivaceus* SCSIO T05 by gene-disruption experiment and bioinformatics analysis.
