**1. Introduction**

Natural products play a dominant role in the discovery of leads for the development of novel drugs to treat human diseases [1]. For the past 30 years, there has been an increasing effort by scientists from many disciplines to identify novel natural products from marine organisms, including marine bacteria, due to their rich biological and chemical diversity [2,3]. With the strong demand to find new antibiotics to solve the antibiotic resistance crisis, research on marine natural products expanded in the last decade to include marine bacteria. Several studies have shown that many novel bioactive compounds were often derived from marine Gram-positive Actinobacteria [3,4].

**Citation:** Wibowo, J.T.; Kellermann, M.Y.; Köck, M.; Putra, M.Y.; Murniasih, T.; Mohr, K.I.; Wink, J.; Praditya, D.F.; Steinmann, E.; Schupp, P.J. Anti-Infective and Antiviral Activity of Valinomycin and Its Analogues from a Sea Cucumber-Associated Bacterium, *Streptomyces* sp. SV 21. *Mar. Drugs* **2021**, *19*, 81. https://doi.org/ 10.3390/md19020081

Academic Editors: Vassilios Roussis and Max Crüsemann Received: 4 December 2020 Accepted: 28 January 2021 Published: 2 February 2021

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Recently, the isolation and fast identification of putatively new bioactive compounds from sea cucumber-associated bacteria have been reported in [5]. Extracts of *Streptomyces* sp. SV 21 showed potent anti-infective activities. Bio-guided fractionation of the bacterial extracts and subsequent MS/MS and NMR experiments revealed valinomycin (**3**), two of its analogues, namely streptodepsipeptide P11B (**1**), streptodepsipeptide P11A (**2**) [6], and one putative new valinomycin analogue named streptodepsipeptide SV21 (**4**). All the compounds (**1**–**4**) exhibited inhibitory activities against bacteria, fungi, and the Hepatitis C Virus (HCV). Streptodepsipeptide SV21 (**4**) had recently been characterized based on exact mass and MS/MS analysis [7]; however, it was neither isolated nor elucidated via NMR nor tested for its bioactivities.

Valinomycin is a common cyclodepsipeptide produced by various soil-derived Actinobacteria, such as *Streptomyces fulvissimus, S. roseochromogenes,* and *S. griseus* var. *flexipartum* [8], as well as from marine *Streptomyces* species associated with the sponges *Axinella polypoides* and *Aplysina aerophoba* [9]. Valinomycin is considered as one of the ionophore antibiotics. This bioactive compound has both a hydrophobic and hydrophilic moiety, which is necessary to bind and shield ions, but also allows the molecule to transport those ions through the lipophilic membrane barrier of living cells. Valinomycin is known to be highly selective for binding potassium ions and thus has the potential to disrupt the intracellular ion concentration of the cell. The probability to transport ions through membranes not only affects osmoregulatory processes, but also affects the homeostasis of the cell, which in turn may result in an increased level of toxicity or even death for the organism [10,11]. Therefore, this cyclodepsipeptide was reported to have many bioactivities, such as antitumor, antibacterial, antibabesia, and antifungal activity [6,9,12,13]. Another interesting bioactivity of valinomycin was its potency against the causative agent of the world's first pandemic in the 21st century, the SARS-CoV virus. Unfortunately, valinomycin also showed enhanced cytotoxicity that prevented the drug to enter the clinical phase [14]. Besides the pharmacological potential, an ecological role also has been reported, as valinomycin is used in chemical defense against pathogens by the leafcutter ant *Acromyrmex echinatior* [15].

In this study, valinomycin (**3**) and its three analogues (**1**, **2**, and **4**) were isolated and characterized based on MS/MS and NMR analysis. In addition, the anti-infective activities of compounds **1**–**4** against multi drug-resistant (MDR) bacteria (*Bacillus subtilis*, *Staphylococcus aureus*), fungi (*Candida albicans*, *Mucor hiemalis*, *Rhodoturula glutinis*) and the Hepatitis C Virus (HCV) were identified.
