Targeting Gram-Negative Cell Surface Assembly for Antibiotic Development

Daniel Kahne of Harvard University, Thomas Bernhardt and Andrew Kruse of Harvard Medical School, and Jiankun Lyu of the Rockefeller University, all in the U.S. will discover novel antibiotics that target essential processes required for cell surface biogenesis in the Gram-negative pathogen Klebsiella pneumoniae. This bacterium and its relatives surround themselves with a multilayered cell surface composed of two membranes - an inner and an outer membrane - sandwiching a cell wall matrix made of the heteropolymer peptidoglycan. This surface architecture prevents many drugs from entering Gram-negative bacterial cells, giving them a high intrinsic resistance to antibiotics. Few therapeutic options are available for treating infections caused by these organisms, especially those that have acquired resistance to carbapenem antibiotics. This project will address the urgent clinical need for novel antibiotics effective against K. pneumoniae and other Gram-negative bacteria by identifying new inhibitors of outer membrane and peptidoglycan biogenesis.