The hitchhiker's guide to the periplasm: unexpected molecular interactions of polymyxin B1 in E. coli
The hitchhiker's guide to the periplasm: unexpected molecular interactions of polymyxin B1 in E. coli
The periplasm of Gram-negative bacteria is a complex, highly crowded molecular environment. Little is known about how antibiotics move across the periplasm and the interactions they experience. Here, atomistic molecular dynamics simulations are used to study the antibiotic polymyxin B1 within models of the periplasm, which are crowded to different extents. We show that PMB1 is likely to be able to “hitchhike” within the periplasm by binding to lipoprotein carriers—a previously unreported passive transport route. The simulations reveal that PMB1 forms both transient and long-lived interactions with proteins, osmolytes, lipids of the outer membrane, and the cell wall, and is rarely uncomplexed when in the periplasm. Furthermore, it can interfere in the conformational dynamics of native proteins. These are important considerations for interpreting its mechanism of action and are likely to also hold for other antibiotics that rely on diffusion to cross the periplasm.
Braun's lipoprotein, OmpA, Pal, antibiotics, cell envelope, cell wall, crowded environment, crowded periplasm, lipoproteins, molecular dynamics, polymyxin B1
444-456.e2
Pedebos, Conrado
87801080-118f-4814-8f86-3524184b0d88
Smith, Iain Peter Shand
16d4b544-dc39-49db-9d14-15b5eb4d295d
Boags, Alister
ec8b83d9-0601-4c97-8acc-3a26349a3076
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
6 May 2021
Pedebos, Conrado
87801080-118f-4814-8f86-3524184b0d88
Smith, Iain Peter Shand
16d4b544-dc39-49db-9d14-15b5eb4d295d
Boags, Alister
ec8b83d9-0601-4c97-8acc-3a26349a3076
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Pedebos, Conrado, Smith, Iain Peter Shand, Boags, Alister and Khalid, Syma
(2021)
The hitchhiker's guide to the periplasm: unexpected molecular interactions of polymyxin B1 in E. coli.
Structure, 29 (5), .
(doi:10.1016/j.str.2021.01.009).
Abstract
The periplasm of Gram-negative bacteria is a complex, highly crowded molecular environment. Little is known about how antibiotics move across the periplasm and the interactions they experience. Here, atomistic molecular dynamics simulations are used to study the antibiotic polymyxin B1 within models of the periplasm, which are crowded to different extents. We show that PMB1 is likely to be able to “hitchhike” within the periplasm by binding to lipoprotein carriers—a previously unreported passive transport route. The simulations reveal that PMB1 forms both transient and long-lived interactions with proteins, osmolytes, lipids of the outer membrane, and the cell wall, and is rarely uncomplexed when in the periplasm. Furthermore, it can interfere in the conformational dynamics of native proteins. These are important considerations for interpreting its mechanism of action and are likely to also hold for other antibiotics that rely on diffusion to cross the periplasm.
Text
Structure_manuscript_PMB1_with_SI
- Accepted Manuscript
More information
Accepted/In Press date: 21 January 2021
e-pub ahead of print date: 11 February 2021
Published date: 6 May 2021
Keywords:
Braun's lipoprotein, OmpA, Pal, antibiotics, cell envelope, cell wall, crowded environment, crowded periplasm, lipoproteins, molecular dynamics, polymyxin B1
Identifiers
Local EPrints ID: 448784
URI: http://eprints.soton.ac.uk/id/eprint/448784
ISSN: 0969-2126
PURE UUID: 3a6df657-8a97-4fb3-8b76-e71f99c3fb17
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Date deposited: 05 May 2021 16:55
Last modified: 26 Nov 2024 02:57
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