The Whole Is Bigger than the Sum of Its Parts: Drug Transport in the Context of Two Membranes with Active Efflux.
Valentin V. Rybenkov,Helen I. Zgurskaya,Chhandosee Ganguly,Inga V. Leus,Zhen Zhang,Mohammad Moniruzzaman +5 more
Reads0
Chats0
TLDR
In this paper, the authors present a review of key experimental and computational approaches to the investigation of transport by individual translocators and in whole cells, summarizes key findings from these studies and outlines implications for antibiotic discovery.Abstract:
Cell envelope plays a dual role in the life of bacteria by simultaneously protecting it from a hostile environment and facilitating access to beneficial molecules. At the heart of this ability lie the restrictive properties of the cellular membrane augmented by efflux transporters, which preclude intracellular penetration of most molecules except with the help of specialized uptake mediators. Recently, kinetic properties of the cell envelope came into focus driven on one hand by the urgent need in new antibiotics and, on the other hand, by experimental and theoretical advances in studies of transmembrane transport. A notable result from these studies is the development of a kinetic formalism that integrates the Michaelis-Menten behavior of individual transporters with transmembrane diffusion and offers a quantitative basis for the analysis of intracellular penetration of bioactive compounds. This review surveys key experimental and computational approaches to the investigation of transport by individual translocators and in whole cells, summarizes key findings from these studies and outlines implications for antibiotic discovery. Special emphasis is placed on Gram-negative bacteria, whose envelope contains two separate membranes. This feature sets these organisms apart from Gram-positive bacteria and eukaryotic cells by providing them with full benefits of the synergy between slow transmembrane diffusion and active efflux.read more
Citations
More filters
Posted ContentDOI
Fast bacterial growth reduces antibiotic accumulation and efficacy
Urszula Łapińska,Margaritis Voliotis,Ka Kiu Lee,Adrian Campey,M. Rhia L. Stone,M. Rhia L. Stone,Wanida Phetsang,Bing Zhang,Krasimira Tsaneva-Atanasova,Mark A. T. Blaskovich,Stefano Pagliara +10 more
TL;DR: In this article, the authors employed microfluidics-based single-cell microscopy, libraries of fluorescent antibiotic probes and mathematical modelling to identify phenotypic variants that avoid antibiotic accumulation within populations of Escherichia coli, Pseudomonas aeruginosa, Burkholderia cenocepacia and Staphylococcus aureus.
Journal ArticleDOI
Fast bacterial growth reduces antibiotic accumulation and efficacy
TL;DR: In this article , the authors employed microfluidics-based single-cell microscopy, libraries of fluorescent antibiotic probes and mathematical modelling to identify phenotypic variants that avoid antibiotic accumulation within populations of Escherichia coli, Pseudomonas aeruginosa, Burkholderia cenocepacia, and Staphylococcus aureus.
Journal ArticleDOI
Clinical Status of Efflux Resistance Mechanisms in Gram-Negative Bacteria
TL;DR: A recent overview of the prevalence of the main efflux pumps observed in clinical practice and an idea of prevalence of this mechanism in the multidrug resistant Gram-negative bacteria is provided in this article.
Journal ArticleDOI
The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes
TL;DR: In this paper, it was shown that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low.
Journal ArticleDOI
MDR Pumps as Crossroads of Resistance: Antibiotics and Bacteriophages
TL;DR: The study and understanding of the mechanisms of the pumps and their contribution to the overall resistance and to the sensitivity to bacteriophages will allow us to either seriously delay the onset of the post-antibiotic era or even prevent it altogether due to phage-antIBiotic synergy.
References
More filters
Journal ArticleDOI
Membrane lipids: where they are and how they behave.
TL;DR: How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functions of their individual membranes?
Journal ArticleDOI
Extended-Connectivity Fingerprints
David Rogers,Mathew Hahn +1 more
TL;DR: A description of their implementation has not previously been presented in the literature, and ECFPs can be very rapidly calculated and can represent an essentially infinite number of different molecular features.
Journal ArticleDOI
Molecular Basis of Bacterial Outer Membrane Permeability Revisited
TL;DR: This review summarizes the development in the field since the previous review and begins to understand how this bilayer of the outer membrane can retard the entry of lipophilic compounds, owing to increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopoly Saccharide structure is modified by environmental conditions.
Journal ArticleDOI
A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.
TL;DR: Observations on the molecular basis of pleiotropic drug resistance are interpreted in terms of a model wherein certain surface glycoproteins control drug permeation by modulating the properties of hydrophobic membrane regions.
Book
Enzyme structure and mechanism
TL;DR: The second edition of this biological reference aimed at undergraduates and graduates is as mentioned in this paper, which covers the structure and mechanism of enzymes, creating a guide to the current understanding of enzymology.