Expanding the chemical space of microbial specialized metabolites: structure elucidation and biosynthesis of novel bioactive natural products from actinomycetes ; Ampliación del espacio químico de metabolitos especializados de origen microbiano. Elucidación estructural y biosíntesis de nuevos productos naturales bioactivos procedentes de actinomicetos

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 ...