Membrane permeation and the rise of antibiotic resistance in Gram-negative bacteria

Supervisors:  Ulrich Zachariae, Samantha Pitt

Project Description
Antimicrobial resistance has evolved into a major global healthcare crisis, threatening to compromise the efficiency of available antibiotic treatments. The World Health Organisation (WHO) has recently named the 12 resistant types of bacteria which require the most urgent action. Amongst these organisms are Neisseria gonorrhoeae and Pseudomonas aeruginosa, some strains of which have become totally resistant against all available antibiotics [1].

In Gram-negative bacteria, such as the examples given above, one of the major obstacles for the development of new antibiotics, or the efficacy of the available drugs, is the poor level of uptake across their dual-membrane cell wall. Inward permeation of the drugs usually requires passage through porins, trimeric channel proteins in the outer membrane, where small mutations are often sufficient to inhibit drug entry and contribute to resistance [2]. Vice versa, active tri-partite efflux pumps, spanning both membranes, efficiently expel a wide range of substances including antimicrobials from the bacterial cells [3].

This project will investigate the major inward and outward permeation pathways in Neisseria gonorrhoeae and other Gram-negative bacteria, including animal and plant pathogens such as Pseudomonas aeruginosa. This will be achieved by studying the interaction of antibiotics with porins and the outer conduits of efflux pumps by a combination of biomolecular simulations including computational electrophysiology and experimental planar lipid bilayer electrophysiology. By achieving a better understanding of the biophysical interactions between the channels and the transported drugs, the aim is to develop a set of rules for optimising the permeability and residence time of drugs in these pathogens. This will be facilitated by the computational analysis of large-scale drug efficacy and bacterial permeation data by chemo- and bioinformatic methods.


1. Rossolini, Gian Maria, et al. "Update on the antibiotic resistance crisis." Current opinion in pharmacology 18 (2014): 56-60.

2. Kutzner, Carsten, et al. "Computational electrophysiology: the molecular dynamics of ion channel permeation and selectivity in atomistic detail." Biophysical journal 101 (2011): 809-817.

3. Fitzpatrick, A.W., Llabrés, S., Neuberger, A., Blaza, J.N., Bai, X.C., Okada, U., Murakami, S., van Veen, H.W., Zachariae, U., Scheres, S.H. and Luisi, B.F., 2017. Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. Nature microbiology, 2, p.17070.