Mechanism of Antibiotic Resistance in Gram-negative Bacteria

Paul Hergenrother, University of Illinois at Urbana-Champaign

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Antibiotic resistance has become a major concern in treatment of bacterial infections. Gramnegative bacteria are particularly troublesome as the lipopolysaccharide-coated outer membrane(OM) presents an additional permeation barrier for antibiotics. Antibiotics that are able to traverse the OM typically do so through membrane proteins called porins. The barrier provided by the OM hampers the development of elective antibiotics against Gram-negative bacteria. We have been developing novel broad-spectrum antibiotics (i.e., active against both Gram-positive and Gramnegative) by chemically modifying antibiotic structure to improve their permeability across the OM of Gram-negative bacteria. Accordingly, Ribocil C (RBC), an antibiotic exclusively active against Gram-positive bacteria was converted to a broad-spectrum antibiotic, Ribocil C-PA (RBC-PA), with the addition of only one amino derivative. In order to characterize the molecular mechanism by which this amine derivative improves permeability, we will use all-atom MD simulations and free-energy calculations for a comparative study of the permeation of RBC and RBC-PA through OmpF. This study will help us understand mechanistic details to guide the design of more effective modifcations and more effective drugs against Gram-negative bacteria.