The Kahne Lab has had a longstanding interest in the problem of antibiotic resistance. Bacteria eventually develop resistance all classes of antibiotics but, for Gram-negative bacteria the problem is especially serious. Unlike Gram-positive bacteria, they have intrinsic resistance to many classes of existing drugs as well. This lack of susceptibility that Gram-negative bacteria have to many existing antibiotics is due to the presence of a double layer of membranes that encases them. In particular, their outer membrane creates an impenetrable barrier that prevents many drugs from reaching their cellular targets. We want to understand the biogenesis of the cell envelope of Gram-negative bacteria, including peptidoglycan biosynthesis and outer membrane assembly. The assembly of this organellar membrane must be accomplished outside the cell in the absence of an obvious energy source. Our group focuses on identifying and understanding the machinery necessary for proper assembly of this membrane barrier, as well as the mechanisms that lead to defects. Because the outer membrane creates an effective permeability barrier to most antibiotics, understanding how to interfere with its assembly could allow repurposing of a huge number of drugs that are currently only active against Gram-positive bacteria. Moreover, because the outer membrane biogenesis machines are conserved and essential they provide new targets for antibiotic discovery as well .