Some very interesting antibiotics have been discovered being produced by unculturable soil microorganisms and previously unstudied microbiomes. See, for example, work from the lab of Kim Lewis at Northeastern University.

Thank you for your contribution! Adam B Shapiro

Many strategies have been developed in this direction, such as isolation from extreme environments and the exploration of microorganisms in associationwith others (endophytes, parasites, symbionts, etc.).

Furthermore, previous studies have shown that nutrient deficiency frequently induces antibiotic production, which in turn initiates a cascade of regulatory processes leading to chemical and morphological differentiation. Of these nutrients, carbon sources that are involved in the inhibition of key enzymes involved in secondary metabolite biosynthesis pathways that impact the production of antibiotics (Sánchez et al. 2010). Carbon limitation impacts the expression of genes involved in morphological differentiation and antibiotic production, especially in the Streptomycesgenus, where glucose has a suppressive effect on the production of actinorhodin and undecylprodigiosin by S. coelicolor, as well as on its morphological differentiation (Romero-Rodríguez et al. 2016). On the other hand, the use of elicitorssuch as nutrients, trace elements, physical parameters, and chemical elicitors, as well as the co-cultivation of microbes and factors affecting epigenetic control, is one of the strategies used to improve the production of natural substances, as proved previously within Streptomyces (Zong et al. 2021 [ taken from my PhD thesis].

The exploration of unconventional sources in the search for new antibiotics is recognized as a promising avenue. Several uncultivable bacteria represent an untapped resource of new drug candidates, but so far it is unknown. However, even with cultivable bacteria, we fail to express several biosynthetic gene clusters (BGCs) under conventional conditions.