Towards a Cipher for Antibiotic Production in Streptomyces

Antimicrobial resistance (AMR) is an increasing threat that requires antibiotics of a new class to tackle the current resistance mechanisms. Streptomyces bacteria are prolific antibiotic producers, with approximately two thirds of all clinical antibiotics being derived from this genus (Barbuto Ferraiuolo et al, 2021). It has been estimated that Streptomyces species have the ability to produce 150,000 bioactive compounds beyond those currently known, and these are likely to include novel antibiotics, some of which may be useful in tackling AMR. These secondary metabolites are encoded by biosynthetic gene clusters (BGCs) that are silent (predicted natural products not expressed) or cryptic (unknown natural products). These BGCs are not expressed under standard laboratory conditions, complicating the study of these natural products with the aim of identifying new, clinically-useful antibiotics. One approach, known as OSMAC (One Strain, Many Compounds), to bypass this issue is by identifying growth conditions that may stimulate BGCs to produce secondary metabolites. This work implemented the OSMAC approach supported by efficient reporter platform GUS to interrogate activation of BGC expression in Streptomyces albidoflavus (albus) and Streptomyces venezueale under different cultivation conditions. This study found that approximately 62% of BGCs in these strains could be activated by the alteration of simple conditions such as the media of cultivation. Using the results of this study and a preceding study of this approach in Streptomyces coelicolor, a small number of conditions efficient in activating the bulk of tested BGCs can be identified. Establishing a platform of a few conditions to test under OSMAC could allow the use of this approach as an efficient platform for antibiotic discovery attempts.