Expanding the chemical space of microbial specialized metabolites: Structure elucidation and biosynthesis of novel bioactive natural products from actinomycetes

Laburpena

The relentless emergence of bacterial resistance to current antibiotics poses a significant health treat, making the development of new effective treatments of vital importance. In this context, the unique structural diversity and biologically optimized functions shaped by the evolution of natural products offer a wide range of drug leads with antimicrobial potential. Historically, these privileged chemical structures have played a valuable role in inspiring drug discovery. Many of the world's most important drugs, including antitumoral, immunosuppressive, and particularly antibiotics were originally discovered from natural sources. Despite the unlimited chemical and biological diversity displayed by secondary metabolites, only a small fraction of the vast reservoir has been surveyed, in which novel compounds are being continuously discovered. With the aim of expanding the chemical space around different groups of bioactive natural products, the present doctoral thesis describes a series of research studies to discover new secondary metabolites from the Fundación MEDINA microorganisms¿ collection. To this end, the following approaches have been employed: i) high-throughput screening (HTS), ii) chemical dereplication, iii) isolation of microbial natural products, iv) structural elucidation through NMR spectroscopy and high-resolution mass spectrometry (HRMS), and v) genome mining to identify talented producers that can biosynthesize new promising bioactive compounds with remarkable structural features. Specifically, this thesis report the discovery of: i) four new meroterpenoids from the napyradiomycin family obtained from a marine-derived Streptomyces, including napyradiomycin D1, the first member of a new structural subtype characterized by a 14-membered ring, which exhibited significant bioactivity against methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis, and the human tumour cell line HepG2; ii) three new cyclic pentapeptides analogous to pentaminomycins (family of natural products including members with selective antibacterial activity against A. baumannii) isolated from a terrestrial Streptomyces, two of which were revealed as the first reported examples of non-ribosomal peptides containing a 2-pyridyl-alanine residue and iii) two new 52-membered glycosylated macrolactones, gargantulides B and C, showing potent growth inhibitory activity against multi-resistant Gram-positive bacteria (e.g., MRSA) and moderate activity against A. baumannii, produced by an Amycolatopsis strain with an extraordinarily large biosynthetic gene cluster of 216 kbp. By exploring microbial sources from both marine and terrestrial habitats, these findings contribute to expanding the chemical diversity of microbial secondary metabolites. These results underscore the vast potential of these compounds as a promising cornerstone for drug development of new bioactive compounds.