Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

Abstract

Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections that are effectively untreatable present a serious threat to public health. The problem is broadly recognized and tackled at both the fundamental and applied levels. This paper summarizes current advances in understanding the molecular bases of the low permeability barrier of Gram-negative pathogens, which is the major obstacle in discovery and development of antibiotics effective against such pathogens. Gaps in knowledge and specific strategies to break this barrier and to achieve potent activities against difficult Gram-negative bacteria are also discussed.

Cyclopropane-1,2-dicarboxylic acids as new tools for the biophysical investigation ofO-acetylserine sulfhydrylases by fluorimetric methods and saturation transfer difference (STD) NMR

“…It is known that an optimal hydrophilic-lipophilic balance (HLB) may enable best penetration across Gram-negative outer membrane [33][34][35] ; therefore, a polar moiety lowering the ClogP can be used to facilitate penetration through S. typhimurium cell wall; (b) serine racemase, a PLPdependent enzyme that shows a good structural similarity with OASS, is inhibited by a series of dicarboxylic derivatives such as modified malonates 36,37 ; (c) the synthetic protocol allowing to prepare such compounds is well established and high structural variability can be obtained starting from easily available materials. First, we synthesized two close analogs of 30, which are compounds 25 and 21, in order to assess whether the carboxylic moiety would better work as an ester or an acid.…”

Breaking the Permeability Barrier of Escherichia coli by Controlled Hyperporination of the Outer Membrane

“…The asymmetric lipopolysaccharide (LPS)-phospholipid bilayer of the outer membrane creates a formidable permeability barrier for both hydrophilic and hydrophobic compounds (1,2). This barrier is further reinforced by active multidrug efflux pumps acting across both the inner and the outer membranes and expelling a broad range of antibiotics from cells (3).…”

“…It is well recognized that the functional interplay between the low permeability barrier of the outer membranes and active drug efflux defines the susceptibility of E. coli to antibiotics (1,2,15). However, the permeation of each class of antibiotics is affected by slow uptake and active efflux to its own degree.…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…Furthermore, it is noticeable that there are fewer antibiotics available for the treatment of infections caused by Gram-negative pathogens compared to Gram-positive ones. The main reason for that issue is the difficulty for antibiotics to cross the outer membrane of Gram-negative bacteria (Zgurskaya et al 2015). The surface of the outer membrane of the Gram-negative bilayer is covered with lipopolysaccharides (LPS), lipidic structures embedded and anchored into the bilayer that consist of three, covalently connected structural elements: A proximal hydrophobic lipid A, a core oligosaccharide region, and a distal O-antigen polysaccharide (Cohen 2011).…”

“…natural products pre-optimized by microorganisms) or for alternative strategies (e.g. active transport machineries of Gram-negative pathogens (Ji et al 2012;Górska et al 2014;Mislin and Schalk 2014) (Saha et al 2013;Wang et al 2014;Johnstone and Nolan 2015) (Page 2013;Górska et al 2014;Mislin and Schalk 2014;Xu et al 2014b;Zgurskaya et al 2015)) need to be intensified significantly. Table 1: Bacterial targets and approved antimicrobial compounds addressing them.…”