Predictive Rules of Efflux Inhibition and Avoidance in Pseudomonas aeruginosa
| Autor: | Valentin V. Rybenkov, Olga Lomovskaya, Sandrasegaram Gnanakaran, Robert H. Cascella, Ruslan Tsivkovski, Cesar A. Lopez, Giuliano Malloci, Helen I. Zgurskaya, Nicolas W. Hengartner, Enrico Margiotta, Rachael A. Mansbach, Napoleon D’Cunha, Alessio Atzori, Sally B. Grindstaff, Paolo Ruggerone, Inga V. Leus, Liam Herndon, Pedro D. Manrique, Jitender Mehla, Attilio Vittorio Vargiu, John K. Walker, Keith M. Haynes |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Protein Conformation alpha-Helical antibiotic resistance medicine.drug_class Peptidomimetic Antibiotics Gene Expression Microbial Sensitivity Tests outer membrane medicine.disease_cause Models Biological Microbiology 03 medical and health sciences Structure-Activity Relationship Antibiotic resistance Virology Drug Resistance Multiple Bacterial medicine Protein Interaction Domains and Motifs machine learning models 030304 developmental biology 0303 health sciences Principal Component Analysis Binding Sites biology 030306 microbiology Pseudomonas aeruginosa Chemistry multidrug efflux Membrane Transport Proteins Transporter Biological Transport Therapeutics and Prevention biology.organism_classification QR1-502 Anti-Bacterial Agents Kinetics Biochemistry Thermodynamics Protein Conformation beta-Strand Efflux Peptidomimetics Bacterial outer membrane Bacteria Research Article Bacterial Outer Membrane Proteins Protein Binding |
| Zdroj: | mBio, Vol 12, Iss 1 (2021) mBio |
| ISSN: | 2150-7511 2161-2129 |
| Popis: | Efflux pump avoidance and inhibition are desired properties for the optimization of antibacterial activities against Gram-negative bacteria. However, molecular and physicochemical interactions defining the interface between compounds and efflux pumps remain poorly understood. We identified properties that correlate with efflux avoidance and inhibition, are predictive of similar features in structurally diverse compounds, and allow researchers to distinguish between efflux substrates, inhibitors, and avoiders in P. aeruginosa. Antibiotic-resistant bacteria rapidly spread in clinical and natural environments and challenge our modern lifestyle. A major component of defense against antibiotics in Gram-negative bacteria is a drug permeation barrier created by active efflux across the outer membrane. We identified molecular determinants defining the propensity of small peptidomimetic molecules to avoid and inhibit efflux pumps in Pseudomonas aeruginosa, a human pathogen notorious for its antibiotic resistance. Combining experimental and computational protocols, we mapped the fate of the compounds from structure-activity relationships through their dynamic behavior in solution, permeation across both the inner and outer membranes, and interaction with MexB, the major efflux transporter of P. aeruginosa. We identified predictors of efflux avoidance and inhibition and demonstrated their power by using a library of traditional antibiotics and compound series and by generating new inhibitors of MexB. The identified predictors will enable the discovery and optimization of antibacterial agents suitable for treatment of P. aeruginosa infections. |
| Databáze: | OpenAIRE |
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