Novel MscL agonists that allow multiple antibiotics cytoplasmic access activate the channel through a common binding site

Wray, Robin; Wang, Junmei; Iscla, Irene; Blount, Paul

doi:10.1371/journal.pone.0228153

Cited by 17 publications

(43 citation statements)

References 61 publications

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“…The robust increase in MscL activity observed in the presence of curcumin was quantified as a significant decrease in MscL pressure activation threshold, from -142.5±16 before to -109.2±24 mmHg after curcumin treatment (n = 4, p≤0.05, Student t-test paired); an increased open probability, as shown in Fig 3B was also apparent. Such an increase in MscL sensitivity is consistent with that seen for gain-of-function mutants [ 13 ] and agonists [ 16 , 17 , 18 ]. These results, combined with the in vivo data above, show that curcumin directly activates the MscL channel in native bacterial membranes.…”

Section: Resultssupporting

confidence: 85%

“…Next, we determined if MscL activation by curcumin was RecA dependent or if these are two independent and complementary mechanisms. Both K + and glutamate are known to flux out the bacterial cells upon MscL activation [ 15 , 18 , 22 ]. We therefore measured the flux of these ions in response to curcumin treatment in cells with and without RecA and MscL; the amount of these ions remaining in the bacterial cells after curcumin treatment was compared to untreated cells.…”

Section: Resultsmentioning

confidence: 99%

“…The second family contains MscS and MscS-related channels; this is a much more diverse channel family for which bacteria often have multiple members that appear to serve slightly different purposes. The inappropriate gating of the large-pore MscL channel can be detrimental to the cell as initially determined by genetic studies [ 12 , 13 ]; more recently, we have shown that known antibiotics [ 14 , 15 ] as well as recently discovered novel small compounds, 011A and K05, open the MscL channel [ 16 , 17 , 18 ] and can increase the potency of well-characterized antibiotics, by increasing cytoplasmic access.…”

Section: Introductionmentioning

confidence: 99%

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Curcumin activation of a bacterial mechanosensitive channel underlies its membrane permeability and adjuvant properties

2021

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Curcumin, a natural compound isolated from the rhizome of turmeric, has been shown to have antibacterial properties. It has several physiological effects on bacteria including an apoptosis-like response involving RecA, membrane permeabilization, inhibiting septation, and it can also work synergistically with other antibiotics. The mechanism by which curcumin permeabilizes the bacterial membrane has been unclear. Most bacterial species contain a Mechanosensitive channel of large conductance, MscL, which serves the function of a biological emergency release valve; these large-pore channels open in response to membrane tension from osmotic shifts and, to avoid cell lysis, allow the release of solutes from the cytoplasm. Here we show that the MscL channel underlies the membrane permeabilization by curcumin as well as its synergistic properties with other antibiotics, by allowing access of antibiotics to the cytoplasm; MscL also appears to have an inhibitory role in septation, which is enhanced when activated by curcumin.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Curcumin activation of a bacterial mechanosensitive channel underlies its membrane permeability and adjuvant properties

2021

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“…However, mechanosensitive channels do not only function to protect a bacterium against osmotic forces, but also have been suggested as well to play a role in antibiotic uptake next to their role in solute efflux 15 , 16 . MscLs provide the main pathway for bacterial uptake of the antibiotic dihydrostreptomycin 17 , which is a large molecule that can induce MscL opening to promote its uptake 15 . Low doses of dihydrostreptomycin inhibit the growth of wild-type bacteria having MscLs, but do not significantly inhibit Δ mscL mutants lacking MscLs 15 .…”

Section: Introductionmentioning

confidence: 99%

Role of adhesion forces in mechanosensitive channel gating in Staphylococcus aureus adhering to surfaces

Carniello

Peterson

Mei

et al. 2020

npj Biofilms Microbiomes

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Mechanosensitive channels in bacterial membranes open or close in response to environmental changes to allow transmembrane transport, including antibiotic uptake and solute efflux. In this paper, we hypothesize that gating of mechanosensitive channels is stimulated by forces through which bacteria adhere to surfaces. Hereto, channel gating is related with adhesion forces to different surfaces of a Staphylococcus aureus strain and its isogenic ΔmscL mutant, deficient in MscL (large) channel gating. Staphylococci becoming fluorescent due to uptake of calcein, increased with adhesion force and were higher in the parent strain (66% when adhering with an adhesion force above 4.0 nN) than in the ΔmscL mutant (40% above 1.2 nN). This suggests that MscL channels open at a higher critical adhesion force than at which physically different, MscS (small) channels open and contribute to transmembrane transport. Uptake of the antibiotic dihydrostreptomycin was monitored by staphylococcal killing. The parent strain exposed to dihydrostreptomycin yielded a CFU reduction of 2.3 log-units when adhering with an adhesion force above 3.5 nN, but CFU reduction remained low (1.0 log-unit) in the mutant, independent of adhesion force. This confirms that large channels open at a higher critical adhesion-force than small channels, as also concluded from calcein transmembrane transport. Collectively, these observations support our hypothesis that adhesion forces to surfaces play an important role, next to other established driving forces, in staphylococcal channel gating. This provides an interesting extension of our understanding of transmembrane antibiotic uptake and solute efflux in infectious staphylococcal biofilms in which bacteria experience adhesion forces from a wide variety of surfaces, like those of other bacteria, tissue cells, or implanted biomaterials.

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“…Such a model suggests that molecular triggers could act as negative allosteric modulators and that tension could be mimicked by molecules in order to activate MS channels (2,3). Indeed, the function of MscL (11)(12)(13) and MscS (5,14) can be modulated by molecule occupancy changes within these pockets. Subtle structural differences within the same regions lead to substantial functional differences in orthologous MscL proteins (15).…”

Section: Introductionmentioning

confidence: 99%

Tension mediated mechanical activation and pocket delipidation lead to an analogous MscL state

Wang

Lane

Kapsalis

et al. 2021

Preprint

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The mechanosensitive channel of large conductance MscL gates in response to tension changes in the membrane to allow the exchange of molecules through its pore. Native ligands that bind and modulate MscL are unknown and trapping an activated state has been challenging. Disruption of lipid access to tension-sensitive transmembrane pockets by modification leads to a concerted structural and functional MscL response. However, it is unknown whether there is structural correlation between tension mediated and molecular activation in mechanosensitive channels. Here, we combine HDX mass spectrometry and ESEEM solvent accessibility measurements on MscL, coupled with molecular dynamics under bilayer tension, to investigate the structural changes associated with the two distinctively derived states. Membrane thinning is not sufficient to hydrate the MscL pore, when lipids are trapped in the pockets, under tensions capable to gate the native channel. Tension and molecule stabilised states present analogous MscL structures, suggesting a link between these two distinct activation mechanisms. These findings could hint at synergistic modes of regulation in mechanosensitive ion channels with implications for their multimodality.

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Novel MscL agonists that allow multiple antibiotics cytoplasmic access activate the channel through a common binding site

Cited by 17 publications

References 61 publications

Curcumin activation of a bacterial mechanosensitive channel underlies its membrane permeability and adjuvant properties

Curcumin activation of a bacterial mechanosensitive channel underlies its membrane permeability and adjuvant properties

Role of adhesion forces in mechanosensitive channel gating in Staphylococcus aureus adhering to surfaces

Tension mediated mechanical activation and pocket delipidation lead to an analogous MscL state

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