Drug Permeation

A major mechanism of antibiotic resistance in Gram-negative bacteria is associated with low permeability of bacterial cell envelopes. The Center seeks to alleviate this problem by identifying chemical rules of compound permeation into bacteria. The main objective of these studies is to find safe and cost-effective ways to guide bioactive compounds into bacterial cells. Once such a way is found, many new antibacterials can be designed even against drug resistant microorganisms.

Cooper, S.J., G. Krishnamoorthy, D. Wolloscheck, J.K. Walker, V.V. Rybenkov, J.M. Parks, and H.I. Zgurskaya, Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa. ACS Infect Dis, 2018. 4(8): p. 1223-1234 DOI: 10.1021/acsinfecdis.8b00036

The low permeability of bacterial cell envelopes is achieved through the synergism between the inherently slow transmembrane diffusion and an active multidrug efflux by transmembrane transporters. As a result, most chemicals are effectively excluded from the cell and are unable to gain access to their intracellular targets. The Center uses a multi-faceted approach to identify chemical features that allow molecules to penetrate into the cell.

The approach is based on kinetic measurement of compound accumulation in bacteria coupled with the use of advanced mathematical modeling of uptake kinetics, the use of genetically modified bacteria for artifact-free variation of the envelope permeability, computer modeling of transmembrane diffusion and efflux transporters, and machine learning to help interpret the results.

Westfall, D.A., G. Krishnamoorthy, D. Wolloscheck, R. Sarkar, H.I. Zgurskaya, and V.V. Rybenkov Bifurcation kinetics of drug uptake by Gram-negative bacteria. PLoS One, 2017. 12(9): p. e0184671 DOI: 10.1371/journal.pone.0184671
Krishnamoorthy, G., I.V. Leus, J.W. Weeks, D. Wolloscheck, V.V. Rybenkov, and H.I. Zgurskaya, Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria. MBio, 2017. 8(5) DOI: 10.1128/mBio.01172-17