New approaches to antimicrobial discovery are needed to address the growing threat of antibiotic resistance. The Streptomyces genus, a proven source of antibiotics, is recognized as having a large reservoir of untapped secondary metabolic genes, many of which are likely to produce uncharacterized compounds. However, most of these compounds are currently inaccessible, as they are not expressed under standard laboratory conditions. Here, we present a novel methodology for activating these "cryptic" metabolites by heterologously expressing a constitutively active pleiotropic regulator. By screening wild Streptomyces isolates, we identified the antibiotic siamycin-I, a lasso peptide that we show is active against multidrug pathogens. We further revealed that siamycin-I interferes with cell wall integrity via lipid II. This new technology has the potential to be broadly applied for use in the discovery of additional "cryptic" metabolites.

WAC04657 is a wild-isolate Streptomyces that has antibiotic activities against multidrug-resistant Gram-negative and Gram-positive pathogens. From a solid-agar culture of this organism we isolated 13-deoxytetrodecamycin, a novel antibacterial molecule. It is one of at least three distinct antimicrobial compounds produced by this strain. The molecule has the molecular formula C 18 H 22 O 5 and is related to the previously discovered compound tetrodecamycin. 13-Deoxytetrodecamycin has potent bioactivity against Gram-positive pathogens including multidrug-resistant Staphylococcus aureus.

The tetrodecamycins are a group of secondary metabolites that are characterized by the presence of a tetronate ring in their structure. Originally discovered for their antibiotic activity against Photobacterium damselae ssp. piscicida, the causative agent of pseudotuberculosis in fish, this family of molecules has also been shown to have potent antibiotic activity against methicillin-resistant Staphylococcus aureus. Due to their small size and highly cyclized nature, they represent an unusual member of the much larger group of bioactive molecules called the tetronates. Herein, we review what is known about the mechanism of action of these molecules and also present a hypothesis for their biosynthesis. A deeper understanding of the tetrodecamycins will provide a more holistic view of the tetronate-family, provide new chemical probes of bacterial biology, and may provide therapeutic lead molecules.

How bacteria adapt to the changing environment within the host is critical for their ability to survive and cause disease. For example, the mammalian host severely restricts iron availability to limit bacterial growth, referred to as nutritional immunity.