Antimicrobial resistance is an imminent threat that is expected to kill 10 million people per year by 2050. Natural products have been a major source of antimicrobial compounds and encompass a chemical space far greater than synthetic chemistry can provide and have evolved over the ages to have biological activities. The natural products produced by Streptomyces have provided us with two-thirds of the antibiotics currently used, as well as chemotherapeutics, antifungals, and immunosuppressants. In recent years, the drug discovery pipeline from Streptomyces has run dry, largely because laboratory culture conditions lack their natural stimuli, resulting in the rediscovery of the same natural products. However, with the advent of modern genomics, we now realize that the genomes of Streptomyces have the have a greater capacity for natural product production than what we have observed, which providing us with the hope of new drug leads.

My doctoral research focused on two aims. First is the concept of eliciting Streptomyces to produce novel natural products; in other words, what triggers the production of natural products. Additional perspectives from ecology, evolution, and regulation evoked the idea that microbe-microbe interactions could be the key. Microscopic observations of the interactions between Streptomyces and yeast suggested that physical contact is essential for elicitation. Genomics, transcriptomics, and proteomics showed that 31% of the silent biosynthetic gene clusters are activated, notably an antifungal polyene cluster, as well as a suite of enzymes capable of digesting the cell wall of yeast. Arguably, Streptomyces can prey on yeast. The differential regulation of a homologous polyene gene clusters further suggested that natural product production is triggered by different ecological needs.

Second, genome mining provides insight into the genetic potential of Actinobacteria to produce natural products via the identification of their gene clusters and is a proven method that aids in drug discovery. Here, I sequenced the genome of a rare Streptomonospora isolate and identified the novel persiamycin gene cluster and its associated product. Moreover, genome mining was applied to publicly available Streptomyces genomes, which resulted in the identification of two new gene clusters that produce the antibiotic komodoquinone B.