Antibiotics from the Microbial Dark Matter
Currenty available antibiotics are largely inactive against dormant persister cells produced by microbial pathogens, and are prone to resistance development. Persisters are responsible for the chronic, relapsing nature of the disease. An even more daunting unsolved problem is the seemingly inevitable development of resistance to all known antibiotics. We find that different natural compounds targeting the Clp protease, acyldepsipeptide and lassomycin, kill persisters and eradicate the pathogen population. Teixobactin, a cell wall synthesis inhibitor was discovered in a screen of uncultured soil bacteria. Teixobactin is the first member of a new class of cell wall acting inhibitors and binds two targets, lipid II, precursor of peptidoglycan, and lipid III, precursor of wall teichoic acid. The targets are not proteins, and there is no resistance development to this compound. Soil microorganisms are likely to harbor many more sterilizing and largely resistance-free compounds. Screening uncultured bacteria provides an effective platform for antibiotic discovery.