Hypoxia-induced production of the cyclolipodepsipeptide BE-43547 by Micromonospora sp. RV43

The urgent need for new antibiotics emphasizes the importance of investigating the many biosynthetic gene clusters that remain silent under standard culture conditions and of assigning functions to the many natural products already discovered. Conventional approaches, such as altering the screening medium composition or culture conditions to trigger production, are often labourious and disconnected from the function of the natural products. In this study, we combine antimicrobial assays and the controlled culture conditions available in benchtop bioreactors to demonstrate that BE-43547, a natural product that exists as a mixture of congeners, is selectively active against Gram-positive bacteria growing anaerobically. Furthermore, we show that the producing organism Micromonospora sp. RV43 activates the biosynthesis of BE-43547 when cultured under low-oxygen conditions. These findings illustrate that linking compound function and regulation cues can provide a powerful strategy for discovering antibiotics with a new mode of action.