Fosmidomycin transport through the phosphate‐specific porins OprO and OprP of <i>Pseudomonas aeruginosa</i>

Piselli, Claudio; Benz, Roland

doi:10.1111/mmi.14693

Cited by 8 publications

(20 citation statements)

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“…One of these porins, OprD (also called OccD1), facilitates translocation of carbapenems ( 18 ), and OpdP/OccD3 might also contribute to this under special circumstances ( 27 ). In addition, OpdH/OccK5 and OprE/OccK8 have been implicated in translocation of the cephalosporin ceftazidime ( 28 , 29 ), whereas OprO and OprP can transport fosmidomycin in vitro ( 30 ). To determine the relevance of these and other porins for the translocation of diverse antimicrobials in intact bacteria, we constructed a series of porin deletion mutants.…”

Section: Resultsmentioning

confidence: 99%

Outer membrane permeability: Antimicrobials and diverse nutrients bypass porins in Pseudomonas aeruginosa

Ude

Tripathi

Buyck

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Gram-negative bacterial pathogens have an outer membrane that restricts entry of molecules into the cell. Water-filled protein channels in the outer membrane, so-called porins, facilitate nutrient uptake and are thought to enable antibiotic entry. Here, we determined the role of porins in a major pathogen, Pseudomonas aeruginosa, by constructing a strain lacking all 40 identifiable porins and 15 strains carrying only a single unique type of porin and characterizing these strains with NMR metabolomics and antimicrobial susceptibility assays. In contrast to common assumptions, all porins were dispensable for Pseudomonas growth in rich medium and consumption of diverse hydrophilic nutrients. However, preferred nutrients with two or more carboxylate groups such as succinate and citrate permeated poorly in the absence of porins. Porins provided efficient translocation pathways for these nutrients with broad and overlapping substrate selectivity while efficiently excluding all tested antibiotics except carbapenems, which partially entered through OprD. Porin-independent permeation of antibiotics through the outer-membrane lipid bilayer was hampered by carboxylate groups, consistent with our nutrient data. Together, these results challenge common assumptions about the role of porins by demonstrating porin-independent permeation of the outer-membrane lipid bilayer as a major pathway for nutrient and drug entry into the bacterial cell.

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Section: Resultsmentioning

confidence: 99%

Outer membrane permeability: Antimicrobials and diverse nutrients bypass porins in Pseudomonas aeruginosa

Ude

Tripathi

Buyck

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Section: Introductionmentioning

confidence: 89%

“…The OprP and OprO protein expression and purification processes were similar to those described previously. ,,,, The E. coli KS26 strains containing the OprP and OprO plasmids, respectively, were grown overnight at 37 °C under shaking (200 RPM) until the optical density (OD 600 ) of the culture reached an OD 600 between 0.5 and 0.7.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…To complement previous studies, , here we report experiments of the fosfomycin permeation through OprP and OprO from P. aeruginosa using electrophysiology similar as it was done in the case of fosmidomycin . Moreover, enhanced sampling molecular dynamics (MD) simulations are presented for the translocation of fosfomycin through OprP and OprO and of fosmidomycin through OprP.…”

Section: Introductionmentioning

confidence: 99%

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Permeation of Fosfomycin through the Phosphate-Specific Channels OprP and OprO of Pseudomonas aeruginosa

et al. 2022

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Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen responsible for many nosocomial infections. It is quite resistant to various antibiotics, caused by the absence of general diffusion pores in the outer membrane. Instead, it contains many substrate-specific channels. Among them are the two phosphate- and pyrophosphate-specific porins OprP and OprO. Phosphonic acid antibiotics such as fosfomycin and fosmidomycin seem to be good candidates for using these channels to enter P. aeruginosa bacteria. Here, we investigated the permeation of fosfomycin through OprP and OprO using electrophysiology and molecular dynamics (MD) simulations. The results were compared to those of the fosmidomycin translocation, for which additional MD simulations were performed. In the electrophysiological approach, we noticed a higher binding affinity of fosfomycin than of fosmidomycin to OprP and OprO. In MD simulations, the ladder of arginine residues and the cluster of lysine residues play an important role in the permeation of fosfomycin through the OprP and OprO channels. Molecular details on the permeation of fosfomycin through OprP and OprO channels were derived from MD simulations and compared to those of fosmidomycin translocation. In summary, this study demonstrates that the selectivity of membrane channels can be employed to improve the permeation of antibiotics into Gram-negative bacteria and especially into resistant P. aeruginosa strains.

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“…Cells can therefore survive in the presence of antimicrobial drugs by reducing permeability of the outer membrane and the activity of porins and by using/increasing multidrug‐efflux pumps. Examples of resistance by modulation of porins/efflux pumps are seen in the Gram‐negative bacteria Stenotrophomonas maltophilia (Calvopiña et al, 2020), Acinetobacter baumannii (Leus et al, 2020), Pseudomonas aeruginosa (Piselli & Benz 2021) and the fungal pathogen Candida lusitanie (Biermann et al, 2021). Acquisition of antibiotic resistance genes from other organisms' plasmids and conjugative transposons is also linked to AMR.…”

mentioning

confidence: 99%

Antimicrobial resistance

Dantas

2022

Molecular Microbiology

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Fosmidomycin transport through the phosphate‐specific porins OprO and OprP of Pseudomonas aeruginosa

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 8 publications

References 69 publications

Outer membrane permeability: Antimicrobials and diverse nutrients bypass porins in Pseudomonas aeruginosa

Outer membrane permeability: Antimicrobials and diverse nutrients bypass porins in Pseudomonas aeruginosa

Permeation of Fosfomycin through the Phosphate-Specific Channels OprP and OprO of Pseudomonas aeruginosa

Antimicrobial resistance

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