Antibiotics resistance caused by efflux pumps

Resistance to antibiotics poses an increasing global threat. Scientists from Jacobs University have been involved in shining light on the molecular details of a multidrug-resistant clinical isolate of the Salmonella bacterium from a patient. Over the course of 20 weeks, whole genome sequencing was performed on the isolates from a patient. The sequencing revealed a mutation which made the bacteria resistant to some antibiotics. Moreover, the researchers discovered that this point mutation is present in an efflux pump which transports antibiotics from the inside to the outside of the cell thus rendering the medication ineffective. The results of the new study have just been published in the journal PNAS.* March 10, 2015
 Together with colleagues from the Universities of Birmingham and Cagliari, computational biophysicists at Jacobs University led by Ulrich Kleinekathöfer, Professor of Theoretical Physics, performed all-atom molecular dynamics simulations on efflux pumps from the Samonella bacterium and its observed mutation. Computational structural analysis suggested that the detected mutation in the efflux pump heavily affected the structure, dynamics, and hydration properties of the binding between antibiotic molecules and pump. The altered binding pocket in the protein structure of the bacterium showed decreased affinity for some drug molecules but also increased binding for others. Prof. Kleinekathöfer explains: “We have found that the mutation of this particular Salmonella bacterium was caused by the substitution of a single amino acid within the efflux pump which in turn made the bacteria resistant to antibiotics,” explained Prof. Kleinekathöfer. “In order to fight antibiotics resistance of bacteria, it is of paramount importance to understand how to increase the amount of antibiotics transported into bacterial cells and how to suppress the undesirable passage of drug molecules out of the bacteria.” The present findings, which have been published recently in the journal PNAS are an important step into obtaining a molecular picture of these underlying processes. Together with his colleague, Mathias Winterhalter, Prof. Ulrich Kleinekathöfer is also part of the New Drugs 4 Bad Bugs (ND4BB) consortium funded within the Innovative Medicines Initiative and a Marie Skłodowska-Curie Training Network funded by the EU. These two European initiatives aim at a detailed understanding of the permeation of antibiotics across cell membranes.  *J. M. A. Blair, V.N. Bavro, V. Ricci, N. Modi, P. Cacciotto, U. Kleinekathӧfer, P. Ruggerone, A. V. Vargiu, A. J. Baylay, H. E. Smith, Y. Brandon, D. Galloway, L. J. V. Piddock, “AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity”, Proc. Natl. Acad. Sci. USA (in press, 2015) DOI:10.1073/pnas.1419939112  Contact: Ulrich Kleinekathöfer | Professor of Theoretical PhysicsEmail: u.kleinekathoefer [at] jacobs-university.de, Tel: +49 421 200-3523