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Higgins Professor of Chemistry and Chemical Biology and of Molecular and Cellular Biology

Daniel Kahne

Higgins Professor of Chemistry and Chemical Biology and of Molecular and Cellular Biology

Professor of Biological Chemistry and Molecular Pharmacology (HMS)

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Dan Kahne lab

Research

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 .

 

Selected Publications

Owens TW, Taylor RJ, Pahil KS, Bertani BR, Ruiz N, Kruse AC, Kahne D. Structural basis of unidirectional export of lipopolysaccharide to the cell surface. Nature2019; 567(7749):550-553.

Rubino FA, Kumar S, Ruiz N, Walker S, Kahne D. Membrane potential is required for MurJ function. J. Am. Chem. Soc. 2018; 140(13):4481-4.

Zhang G, Baidin V, Pahil K, Moison E, Tomasek D, Ramadoss NS, Chatterjee AK, McNamara CW, Young TS, Schultz PG, Meredith TC, Kahne D. Cell-based screen for discovering lipopolysaccharide biogenesis inhibitors. Proc. Natl. Acad. Sci. USA 2018; 115(26):6834-9.

Sherman DJ, Xie R, Taylor RJ, George AH, Okuda S, Foster PJ, Needleman DJ, Kahne D. Lipopolysaccharide is transported to the cell surface by a membrane-to-membrane protein bridge. Science 2018; 798-801.

Wzorek JS, Lee J, Tomasek D, Hagan CL, Kahne DE.  Membrane integration of an essential beta-barrel protein prerequires burial of an extracellular loop. Proc. Natl. Acad. Sci. USA 2017; 114(10):2598-2603.