Antibiotic Substrate Selectivity of Pseudomonas aeruginosa MexY and MexB Efflux Systems Is Determined by a Goldilocks Affinity

Debayan Dey; Logan G Kavanaugh; Graeme L Conn

doi:10.1128/AAC.00496-20

Antibiotic Substrate Selectivity of Pseudomonas aeruginosa MexY and MexB Efflux Systems Is Determined by a Goldilocks Affinity

Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00496-20. doi: 10.1128/AAC.00496-20. Print 2020 Jul 22.

Authors

Debayan Dey¹, Logan G Kavanaugh^{1

2}, Graeme L Conn^{3

4}

Affiliations

¹ Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.
² Graduate Program in Microbiology and Molecular Genetics, Emory University, Atlanta, Georgia, USA.
³ Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA [email protected].
⁴ Emory Antibiotic Resistance Center, Emory University, Atlanta, Georgia, USA.

Abstract

Resistance-nodulation-division (RND) efflux pumps are important contributors to bacterial antibiotic resistance. In this study, we combined evolutionary sequence analyses, computational structural modeling, and ligand docking to develop a framework that can explain the known antibiotic substrate selectivity differences between two Pseudomonas aeruginosa RND transporters, MexY and MexB. For efficient efflux, antibiotic substrates must possess a "Goldilocks affinity": binding strong enough to allow interaction with transporter but not so tight as to impede movement through the pump.

Keywords: Pseudomonas aeruginosa; antibiotic resistance; computer modeling; efflux pumps; phylogenetic analysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents* / pharmacology
Bacterial Outer Membrane Proteins / genetics
Bacterial Outer Membrane Proteins / metabolism
Drug Resistance, Bacterial
Membrane Transport Proteins / genetics
Pseudomonas aeruginosa* / genetics
Pseudomonas aeruginosa* / metabolism

Substances

Anti-Bacterial Agents
Bacterial Outer Membrane Proteins
Membrane Transport Proteins