This study aimed to assess the influence of nutrient media content on the production of antibiotics and the ability of water fungi isolated from lake Baikal to synthesize novel natural products. Interest in this topic stems from the high demand for new drugs, and studies are carried out via the screening of new natural products with biological activity produced by unstudied or extremophilic microorganisms. For this study, a strain of Penicillium sp. was isolated from endemic Baikal phytophagous amphipod species. Here, we identified natural products using the following classical assays: biotechnological cultivation, MALDI identification of the strain, natural product extraction, antimicrobial activity determination, and modern methods such as HPLC-MS for the dereplication and description of natural products. It was found that many detected metabolites were not included in the most extensive database. Most of the identified metabolites were characterized by their biological activity and demonstrated antibiotic activity against model Gram-positive and Gram-negative bacteria. The isolated strain of water fungus produced penicolinate B, meleagrin A, austinoneol A, andrastin A, and other natural products. Additionally, we show that the synthesis of low-molecular-weight natural products depends on the composition of the microbiological nutrient media used for cultivation. Thus, although the golden age of antibiotics ended many years ago and microscopic fungi are well studied producers of known antibiotics, the water fungi of the Lake Baikal ecosystem possess great potential in the search for new natural products for the development of new drugs. These natural products can become new pharmaceuticals and can be used in therapy to treat new diseases such as SARS, MERS, H5N1, etc.