The pharmacology of the mechanosensitive channels of Escherichia coli

Thom Nguyen

Research output: ThesisDoctoral Thesis

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Mechanosensitive (MS) channels are a class of ion channels which are gated by membrane stretch. The mechanosensitive channel of large conductance (MscL) of the bacterium E.coli has become a prototype MS channel for studying structure-function relationships in this class of ion channels. MscL homologues have commonly been found in Gram-negative and Gram-positive bacterial strains forming a sub-family of a larger family of MS class of ion channels encompassing prokaryotes (bacteria and archaea) as well as cell-walled eukaryotes (fungi and plants). MscL and its homologues have been found to play an important role in osmoregulation of bacterial cells. Though the MS channels of bacteria have been thoroughly studied, little is known about the pharmacology of these channels. This thesis has one general aim, that is, to identify compounds which are able to gate and/or alter the gating of the MS channels of bacteria in particular, the MscL of E. coli. Using the patch-clamp technique, potential compounds mostly identified via in-silico techniques were examined to observe the effects on MscL reconstituted in artificial lipid membranes and MscS in giant bacterial spheroplasts. The compounds were tested for the ability to spontaneously gate the MscL and MscS and/or alter the Boltzmann distribution parameters of the MscL, indicative of an effect on the gating of MscL. Compounds showing potential as MscL activators were then examined for in-vivo effects using different growth assays. The effects of parabens, gallates, eriochrome cyanine R, brilliant green, deoxycholic acid are reported. Of these compounds, parabens and eriochrome cyanine R showed the most encouraging results. Identification of MS channel gate ligands not only benefits structural studies as tetrodotoxin has for the voltage-sensitive sodium channel, these compounds could also V potentially serve as base compounds for novel antibiotics which would target the MS channels of bacteria. Since the MS channels of bacteria serve as safety valves for the bacterium, gating during exposure to a hypo-osmotic challenge such as rain to release excessive cellular turgor, a pharmacological agent that could impair the gating of the MS channels releasing essential cytoplasmic osmolytes, would cause the growth impairment or death of the bacterium. With the rise in multi-drug resistant bacteria, continual development of novel antibiotics is crucial.
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2007


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