Biophysical Society Thematic Meeting | Stockholm 2022
Physical and Quantitative Approaches to Overcome Antibiotic Resistance
Poster Abstracts
13-POS Board 13 NOVEL ANTIBIOTICS TARGET BAMA LATERAL GATE OPENING AS MECHANISM OF ACTION Katie M. Kuo 1 ; Jinchan Liu 3 ; Anna Pavlova 2 ; James C Gumbart 2 ; 1 Georgia Institute of Technology, School of Chemistry and Biochemistry, Atlanta, GA, USA 2 Georgia Institute of Technology, School of Physics, Atlanta, GA, USA 3 Yale University, Department of Chemistry, New Haven, CT, USA BamA, the core component of the β -barrel assembly machinery (BAM) complex, is an outer membrane protein (OMP) in Gram-negative bacteria. Its function is to insert and fold substrate OMPs into the outer membrane (OM). Evidence suggests that BamA follows the asymmetric hybrid- barrel model, where the first strand of BamA preferentially interacts with the substrate OMP compared to the last strand. More specifically, the threading model states that the separation of the first and last strands of BamA, known as lateral gate opening, allows nascent substrate OMP β - strands to sequentially fold through β -augmentation. Recently, multiple lead compounds that target and interfere with BamA function have been identified. In our models and simulations of BamA with the lead compounds bound, we found that the lateral gate was affected. In addition, we simulated mutants of BamA that are resistant to one or more of the identified lead compounds for 20 µs each in aggregate, for a total time of 100 µs. In these simulations, we observed a notably larger degree and/or frequency of opening of BamA’s lateral gate, suggesting that the mutations grant resistance by making the gate more permissive. The lead compounds act by inhibiting BamA lateral gate opening and, thus, subsequent OMP folding and insertion. These simulations validate the lateral gate opening as a mechanism of action to target in antibiotic development.
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