Predictive rules of efflux inhibition and avoidance in Pseudomonas aeruginosa

Jitender Mehla;Giuliano Malloci;Rachael Mansbach;Cesar A. López;Ruslan Tsivkovski;Keith Haynes;Inga V. Leus;Sally B. Grindstaff;Robert H. Cascella;Napoleon D’Cunha;Liam Herndon;Nicolas W. Hengartner;Enrico Margiotta;Alessio Atzori;Attilio V. Vargiu;Pedro D. Manrique;John K. Walker;Olga Lomovskaya;Paolo Ruggerone;S. Gnanakaran;Valentin V. Rybenkov;Helen I. Zgurskaya

2021-01-01

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Abstract

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 anti-bacterial agents suitable for treatment of P. aeruginosa infections.