Toward Understanding the Outer Membrane Uptake of Small Molecules by Pseudomonas aeruginosa

Eren, Elif; Parkin, Jamie; Adelanwa, Ayodele; Cheneke, Belete R.; Movileanu, Liviu; Khalid, Syma; Berg, Bert van den

doi:10.1074/jbc.m113.463570

Cited by 52 publications

(77 citation statements)

References 60 publications

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“…Molecular simulations have been used to model the overall kinetics of translocation that result from the multiple transient interactions between a porin and its substrate [31][32][33] . A key challenge to in silico approaches for studying kinetic processes is the need for relatively long and atomically detailed simulations to adequately sample key interactions that contribute to the free-energy profile for translocation.…”

Section: Getting Drugs Into Bugsmentioning

confidence: 99%

ESKAPEing the labyrinth of antibacterial discovery

Tommasi

Brown

Walkup

et al. 2015

Nat Rev Drug Discov

518

503

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Antimicrobial drug resistance is a growing threat to global public health. Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals. Although some promising agents are in the pipeline, there is an urgent need for new antibiotic scaffolds. However, antibacterial researchers have struggled to identify new small molecules with meaningful cellular activity, especially those effective against multidrug-resistant Gram-negative pathogens. This difficulty ultimately stems from an incomplete understanding of efflux systems and compound permeation through bacterial membranes. This Opinion article describes findings from target-based and phenotypic screening efforts carried out at AstraZeneca over the past decade, discusses some of the subsequent chemistry challenges and concludes with a description of new approaches comprising a combination of computational modelling and advanced biological tools which may pave the way towards the discovery of new antibacterial agents.

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Section: Getting Drugs Into Bugsmentioning

confidence: 99%

ESKAPEing the labyrinth of antibacterial discovery

Tommasi

Brown

Walkup

et al. 2015

Nat Rev Drug Discov

518

503

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“…However, small hydrophilic compounds, like imipenem, require outer membrane porins for cell entry (Eren et al, 2013). In P. aeruginosa , the OprD porin enables the entry of positively charged aminoacids and imipenem (Trias and Nikaido, 1990).…”

Section: Resultsmentioning

confidence: 99%

Defining the Roles of the Cation Diffusion Facilitators in Fe2+/Zn2+ Homeostasis and Establishment of Their Participation in Virulence in Pseudomonas aeruginosa

Salusso

Raimunda

2017

Front. Cell. Infect. Microbiol.

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Transporters of the cation diffusion facilitator (CDF) family form dimers that export transition metals from the cytosol. The opportunistic pathogen Pseudomonas aeruginosa encodes three homologous CDF genes, czcD (PA0397), aitP (PA1297), and yiiP (PA3963). The three proteins are required for virulence in a plant host model. Disruption of the aitP gene leads to higher Fe2+ and Co2+ sensitivity together with an intracellular accumulation of these ions and to a decreased survival in presence of H2O2. Strains lacking czcD and yiiP showed low Zn2+ sensitivity. However, in iron-rich media and in the presence of Zn2+ these strains secreted higher levels of the iron chelator pyoverdine. Disruption of czcD and yiiP in a non-pyoverdine producer strain and lacking the Zn2+-transporting ATPase, increased the Zn2+ sensitivity and the accumulation of this ion. Most importantly, independent of the pyoverdine production strains lacking CzcD or YiiP, presented lower resistance to imipenem, ciprofloxacin, chloramphenicol, and gentamicin. These observations correlated with a lower survival rate upon EDTA-lysozyme treatment and overexpression of OprN and OprD porins. We hypothesize that while AitP is an Fe2+/Co2+ efflux transporter required for Fe2+ homeostasis, and ultimately redox stress handling, CzcD, and YiiP export Zn2+ to the periplasm for proper Zn2+-dependent signaling regulating outer membrane stability and therefore antibiotic tolerance.

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“…Characteristic of most OM proteins is a b-barrel structure spanning the membrane, as well as long and charged EC loops. The orientation of these EC loops often plays a significant role in nutrient uptake across the OM (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Role of the Native Outer-Membrane Environment on the Transporter BtuB

Balusek

Gumbart

2016

Biophysical Journal

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BtuB is a TonB-dependent transporter that permits the high-affinity binding and transport of cobalamin (CBL), or vitamin B 12 , across the asymmetric outer membrane (OM) of Gram-negative bacteria. It has been shown that Ca 2þ binding is necessary for high-affinity binding of CBL to BtuB, and earlier simulations suggested that calcium ions serve to stabilize key substrate-binding extracellular loops. However, those simulations did not account for the lipopolysaccharides in the OM. To illuminate the roles of both Ca 2þ and lipopolysaccharides in protein functionality, we performed simulations of apo and Ca 2þ -loaded BtuB in symmetric and asymmetric bilayers. The simulations reveal that the oligosaccharides of LPS stabilize the extracellular loops to some degree, apparently obviating the need for Ca 2þ . However, it is shown that Ca 2þ ions stabilize a key substrate-binding loop to an even greater degree, as well as reposition specific CBL-binding residues, bringing them closer to the organization found in the CBL-bound structure. These results indicate the importance of including realistic membrane models when simulating outer-membrane proteins.

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Toward Understanding the Outer Membrane Uptake of Small Molecules by Pseudomonas aeruginosa

Cited by 52 publications

References 60 publications

ESKAPEing the labyrinth of antibacterial discovery

ESKAPEing the labyrinth of antibacterial discovery

Defining the Roles of the Cation Diffusion Facilitators in Fe2+/Zn2+ Homeostasis and Establishment of Their Participation in Virulence in Pseudomonas aeruginosa

Role of the Native Outer-Membrane Environment on the Transporter BtuB

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