Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 31, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2107644118
Keywords
membrane transport; bacterial outer membrane; lipid bilayer; diffusion; antimicrobial resistance
Categories
Funding
- European Union
- European Federation of Pharmaceutical Industries and Associations (IMI, ND4BB-TRANSLOCATION)
- Swiss National Science Foundation [310030_156818, 310030_182315, NRP 72-177449]
- Biozentrum PhD fellowships
- Swiss National Science Foundation (SNF) [310030_156818, 310030_182315] Funding Source: Swiss National Science Foundation (SNF)
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This study found that all porins in Pseudomonas aeruginosa were not essential for bacterial growth in rich medium and consumption of diverse hydrophilic nutrients. However, nutrients with multiple carboxylate groups permeated poorly in the absence of porins. Porins provided efficient pathways for nutrient uptake while effectively excluding most antibiotics except carbapenems, with outer-membrane lipid bilayer serving as a major pathway for nutrient and drug entry into the bacterial cell.
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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