**1. Introduction**

Sponges host abundant and remarkable diverse microbial communities [1] that exhibit biological complexity similar to the human microbiome [2,3]. Cyanobacteria are an ancient lineage of photosynthetic prokaryotes demonstrating ecological key roles (e.g., oxygen production, nitrogen fixation, carbon flux) in a broad range of habitats, including sponges [4,5], with which they are often found in symbiosis (cyanobionts). Several approaches including whole-genome sequencing of symbiotic microbes and metagenomic binning have provided insights into the functional potential of the symbionts [6,7]. For instance, it has been shown that across sponge-associated bacteria taxa there are pathways involved in carbon fixation, B-vitamin synthesis, taurine metabolism, sulfite oxidation, and most steps of nitrogen metabolism [7,8]. *Candidatus Synechococcus spongiarum,* a widespread (yet uncultivated) sponge symbiont, has specific adaptations to life inside sponges [9]. This obligate cyanobiont showed extreme genome reduction [9], similarly to other bacterial sponge symbionts such as *Candidatus Endohaliclona renieramycinifaciens* [10]. Genome reduction is the major genomic feature of bacterial symbionts [11] and is thought to be a process that reduces the cost of genome replication [12].

**Citation:** Konstantinou, D.; Popin, R.V.; Fewer, D.P.; Sivonen, K.; Gkelis, S. Genome Reduction and Secondary Metabolism of the Marine Sponge-Associated Cyanobacterium *Leptothoe*. *Mar. Drugs* **2021**, *19*, 298. https://doi.org/10.3390/md19060298

Academic Editor: Max Crüsemann

Received: 30 April 2021 Accepted: 21 May 2021 Published: 24 May 2021

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Cyanobacteria are a prolific source of natural products with complex chemical structures and interesting bioactivities [13]. Advances in genomics have greatly expanded our knowledge and understanding of cyanobacterial natural product biosynthesis [13] with known natural products linked to biosynthetic gene clusters and new natural products discovered through genome mining (e.g., [14–17]). However, the majority of natural products from cyanobacteria are described from a relative limited number of genera [13]. This phenomenon is attributed to problems with cyanobacterial taxonomy that obfuscates the true distribution of natural products in marine cyanobacteria.

Marine sponges are also prolific sources of natural products of great interest for drug development, contributing to nearly 30% (more than 4850 compounds) of all marine natural products discovered [18]. Sponge-associated bacteria are widely thought to be responsible for sponge natural product diversity [2,3,19], with cyanobacteria being among the major producers [20].

Sponge-associated members of the newly described marine cyanobacterium *Leptothoe* [21,22] were found to be highly cytotoxic against human breast, skin, and colon cancer epithelial cells [23]. Extracts of *Le. kymatousa* TAU-MAC 1615 were found to have antibacterial activity [23]. In this study, we sequenced two draft *Leptothoe* genomes, *Le. kymatousa* TAU-MAC 1615 and *Le. spongobia* TAU-MAC 1115, previously isolated form the marine sponges *Chondrilla nucula* and *Acanthella acuta*, respectively [21,24]. We performed comparative genomic analyses of sponge-associated, other host-associated and free-living members of *Leptothoe* genus, and other marine cyanobacterial genera, aiming to (a) identify symbiosis factors and (b) gain insight into their natural product biosynthetic potential.
