Predictive Rules of Efflux Inhibition and Avoidance in Pseudomonas aeruginosa
Jitender Mehla, Giuliano Malloci, Rachael A. Mansbach, César A. López, Ruslan Tsivkovski, Keith M. Haynes, Inga V. Leus, Sally B. Grindstaff, Robert H. Cascella, Napoleon D’Cunha, Liam Herndon, Nicolas 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
Abstract
The developed predictive models are based on the descriptors representative of different clusters comprising a physically intuitive combination of properties. Molecular shape (represented by acylindricity), amphiphilicity (anisotropic polarizability), aromaticity (number of aromatic rings), and the partition coefficient (LogD) are physicochemical predictors of efflux inhibitors, whereas interactions with Pro668 and Leu674 residues of MexB distinguish between inhibitors/substrates and efflux avoiders. The predictive models and efflux rules are applicable to compounds with unrelated chemical scaffolds and pave the way for development of compounds with the desired efflux interface properties.