Amazing stuff! Are we cracking the defenses of bacteria? Is this the bacterial immune system?
"Just as bailing out water with a bucket can save a sinking boat, certain cells have their own special technology for expelling toxins. Unfortunately, “toxins” can include antibiotic treatments. ...
uncovered the equipment that enables bacteria to survive exposure to antibiotics: a shuttling mechanism that helps a complex of proteins pump out a wide spectrum of antibiotics along with other physiological substrates from the cell. ...
Some bacteria are more resistant to antibiotics than others, with so-called gram-negative bacteria being particularly resilient because they have an extra membrane to armor themselves. They also have a sophisticated plumbing system in the form of a three-part protein complex – MacAB-TolC – that spans the cell’s inner and outer membranes, as well as the periplasm that connects them. Each of the three key proteins occupies a different location: TolC on the outer membrane, MacB on the inner membrane and MacA in the periplasm, although it is anchored on the inner membrane.
This “tripartite” protein complex, also known as a multidrug efflux pump, forms a conduit that drains out not only antibiotics but also virulence factors – i.e., molecules that are produced by the bacterial cell itself and can infect or otherwise compromise its host. ..."
From the highlights and abstract:
"Highlights
• Single-molecule imaging reveals imbalanced stoichiometry of MacAB-TolC components in vivo
• Excess MacB shows spatiotemporal behaviors for efficient substrate sequestration and efflux
• The limiting MacA can disassemble from MacAB-TolC and shuttle among clustered MacB
• Chemical or physical perturbation can compromise MacAB-TolC function
Summary
Multidrug efflux pumps confer not only antibiotic resistance to bacteria but also cell proliferation.
In gram-negative bacteria, the ATP-binding cassette (ABC)-family transporter MacB, the adaptor protein MacA, and the outer membrane protein TolC form the MacA6:MacB2:TolC3 assembly to extrude antibiotics and virulence factors.
Here, using quantitative single-molecule single-cell imaging, we uncover that, in E. coli cells, there is a large excess of MacB (and TolC) driving the limiting adaptor protein MacA mostly into the MacAB-TolC assembly.
Moreover, the excess MacB transporters can dynamically cluster around the assembly, and MacA can dynamically disassemble from the MacAB-TolC assembly, leading to an adaptor protein shuttling mechanism for efficient substrate sequestration from the periplasm toward efflux.
We further show that both MacB clustering and MacAB-TolC assembly can be perturbed chemically or physically via microfluidics-based extrusion loading for compromised antibiotic tolerance. These insights may provide opportunities for countering the activities of multidrug efflux systems for antimicrobial treatments."
Graphical abstract
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