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Structural shifts in TolC facilitate Efflux-Mediated ß-lactam resistance.
Kantarcioglu, Isik; Gaszek, Ilona K; Guclu, Tandac F; Yildiz, M Sadik; Atilgan, Ali Rana; Toprak, Erdal; Atilgan, Canan.
Afiliação
  • Kantarcioglu I; Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey.
  • Gaszek IK; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Guclu TF; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Yildiz MS; Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey.
  • Atilgan AR; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Toprak E; Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey.
  • Atilgan C; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA. erdal.toprak@utsouthwestern.edu.
Commun Biol ; 7(1): 1051, 2024 Aug 26.
Article em En | MEDLINE | ID: mdl-39187619
ABSTRACT
Efflux-mediated ß-lactam resistance is a major public health concern, reducing the effectiveness of ß-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 ß-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 ß-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas da Membrana Bacteriana Externa / Resistência beta-Lactâmica / Simulação de Dinâmica Molecular / Antibacterianos Idioma: En Revista: Commun Biol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Turquia País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
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XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas da Membrana Bacteriana Externa / Resistência beta-Lactâmica / Simulação de Dinâmica Molecular / Antibacterianos Idioma: En Revista: Commun Biol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Turquia País de publicação: Reino Unido