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Many microbial secondary metabolites have been studied for decades primarily because of their antimicrobial properties. However, several of these metabolites also possess non-antimicrobial functions, both influencing the physiology of the producer and their ecological neighbors. An example of a versatile bacterial secondary metabolite with multiple functions is the tropone derivative tropodithietic acid (TDA). TDA is a broad-spectrum antimicrobial compound produced by several members of the Rhodobacteraceae family, a major marine bacterial lineage, within the genera Phaeobacter, Tritonibacter and Pseudovibrio. The production of TDA is governed by the mode of growth and influenced by the availability of nutrient sources. The antibacterial effect of TDA is caused by disruption of the proton motive force of target microorganisms and, potentially, by its iron-chelating properties. TDA also acts as a signaling molecule, affecting gene expression in other bacteria, and altering phenotypic traits such as motility, biofilm formation, and antibiotic production in the producer. In microbial communities, TDA-producing bacteria cause a reduction of the relative abundance of closely related species and some fast-growing heterotrophic bacteria. Here, we summarize the current understanding of the chemical ecology of TDA, including the environmental niches of TDA-producing bacteria, and the molecular mechanisms governing the function and regulation of TDA.

Bacillus subtilis produces a wide range of secondary metabolites providing diverse plant growth-promoting and biocontrol abilities. These secondary metabolites include nonribosomal peptides with strong antimicrobial properties, causing either cell lysis, pore formation in fungal membranes, inhibition of certain enzymes, or bacterial protein synthesis. However, the natural products of B. subtilis are mostly studied either in laboratory strains or in individual isolates, and therefore, a comparative overview of secondary metabolites from various environmental B. subtilis strains is missing. In this study, we isolated 23 B. subtilis strains from 11 sampling sites, compared the fungal inhibition profiles of wild types and their nonribosomal peptide mutants, followed the production of targeted lipopeptides, and determined the complete genomes of 13 soil isolates. We discovered that nonribosomal peptide production varied among B. subtilis strains coisolated from the same soil samples. In vitro antagonism assays revealed that biocontrol properties depend on the targeted plant pathogenic fungus and the tested B. subtilis isolate. While plipastatin alone is sufficient to inhibit Fusarium spp., a combination of plipastatin and surfactin is required to hinder growth of Botrytis cinerea. Detailed genomic analysis revealed that altered nonribosomal peptide production profiles in specific isolates are due to missing core genes, nonsense mutation, or potentially altered gene regulation. Our study combines microbiological antagonism assays with chemical nonribosomal peptide detection and biosynthetic gene cluster predictions in diverse B. subtilis soil isolates to provide a broader overview of the secondary metabolite chemodiversity of B. subtilis. IMPORTANCE Secondary or specialized metabolites with antimicrobial activities define the biocontrol properties of microorganisms. Members of the Bacillus

Secondary metabolites have an important impact on the biocontrol potential of soil-derived microbes. In addition, various microbe-produced chemicals have been suggested to impact the development and phenotypic differentiation of bacteria, including biofilms. The non-ribosomal synthesized lipopeptide of Bacillus subtilis, surfactin, has been described to impact the plant promoting capacity of the bacterium. Here, we investigated the impact of surfactin production on biofilm formation of B. subtilis using the laboratory model systems; pellicle formation at the air-medium interface and architecturally complex colony development, in addition to plant root-associated biofilms. We found that the production of surfactin by B. subtilis is not essential for pellicle biofilm formation neither in the well-studied strain, NCIB 3610, nor in the newly isolated environmental strains, but lack of surfactin reduces colony expansion. Further, plant root colonization was comparable both in the presence or absence of surfactin synthesis. Our results suggest that surfactin-related biocontrol and plant promotion in B. subtilis strains are independent of biofilm formation.

Natural products are the main source of approved medicines with more than half of the drugs on the market today being either natural products or natural product derivatives. Moreover, a significant number of these drugs are of plant origins. However, it has been estimated that of the >422,000 plant species currently described, only 15% of this plant diversity have been phytochemically explored. Therefore, there still exists a huge potential in the plant kingdom for the discovery of new chemistry, some of which may result in the identification of lead compounds or drugs for the pharmaceutical industry. Several notable examples of plant-derived natural product drugs are the anticancer compounds vinblastine, vincristine, and paclitaxel, the antimalarial agents artemisinin and quinine, and the Alzheimer drugs galantamine and huperzine A. In regards to plant-derived lead compounds, two pertinent examples include camptothecin, which lead to the development of the anticancer agents, topotecan and irinotecan, and papaverine, which was the lead model for the antihypertension verapamil. The Celastraceae plant family is found worldwide, especially in tropical and subtropical regions; currently there are 88 genera and 1300 species belonging to this flowering plants family. Various molecules possessing numerous biological activities have been reported from Celastraceae. One noteworthy example of an interesting natural product and cancer lead compound from Celastraceae is the alkaloid maytansine, which was further developed into the antibody drug conjugate treatment, transtuzumab emtansine, and is currently used for breast cancer treatment. However, the characteristic secondary metabolites of Celastraceae are the dihydro-[beta]-agarofuran sesquiterpenoids, which have been reported in the literature as both chemotaxonomic markers and privileged structures. The L-type amino acid transporters (LATs) are responsible for the uptake of various amino acids (including leucine) into cells, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Environment and Sc, Science, Environment, Engineering and Technology, Full Text