Structural shifts in TolC facilitate Efflux-Mediated β-lactam resistance.
Isik KantarciogluIlona K GaszekTandac F GucluM Sadik YildizAli Rana AtilganErdal ToprakCanan AtilganPublished in: Communications biology (2024)
Efflux-mediated β-lactam resistance is a major public health concern, reducing the effectiveness of β-lactam antibiotics against many bacteria. Structural analyses show the efflux protein TolC in Gram-negative bacteria acts as a channel for antibiotics, impacting bacterial susceptibility and virulence. This study examines β-lactam drug efflux mediated by TolC using experimental and computational methods. Molecular dynamics simulations of drug-free TolC reveal essential movements and key residues involved in TolC opening. A whole-gene-saturation mutagenesis assay, mutating each TolC residue and measuring fitness effects under β-lactam selection, is performed. Here we show the TolC-mediated efflux of three antibiotics: oxacillin, piperacillin, and carbenicillin. Steered molecular dynamics simulations identify general and drug-specific efflux mechanisms, revealing key positions at TolC's periplasmic entry affecting efflux motions. Our findings provide insights into TolC's structural dynamics, aiding the design of new antibiotics to overcome bacterial efflux mechanisms.
Keyphrases
- molecular dynamics simulations
- public health
- molecular docking
- gram negative
- escherichia coli
- pseudomonas aeruginosa
- genome wide
- systematic review
- randomized controlled trial
- body composition
- staphylococcus aureus
- crispr cas
- physical activity
- high throughput
- dna methylation
- transcription factor
- small molecule
- cystic fibrosis
- single cell
- amino acid
- global health