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Disulfide bonds are critical for stabilizing cell division, cell envelope biogenesis, and antibiotic resistance proteins in mycobacteria

ABSTRACT: Mycobacterium, including Mycobacterium tuberculosis, the etiological agent of tuberculosis, have a unique cell envelope critical for their survival and antibacterial resistance. The cell envelope's assembly and maintenance influence permeability, making it a key target against multidrug resistant strains. Disulfide bond (SB) formation is crucial for the folding of cell envelope proteins The DSB pathway in mycobacteria includes two enzymes, DsbA and VKOR, required for survival. Using bioinformatics and cystine prfiling proteomics, we identified cell envelope proteins dependent on DSBs. We validated via in vivo alkylation, that key proteins like LamA (MmpS3, PstP, LpqW, and EmbB rely on DSBs for stability. Their stability is disrupted in the Delta VKOR mutant or by VKOR inhibition. Thus targeting DsbA and VKOR systems could compromise both cell division and mycomembrane integrity. These findings emphasize the potential of DSB inhibition as a novel strategy to combat mycobacterial infections.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mycobacterium Smegmatis Str. Mc2 155 (ncbitaxon:246196)

SUBMITTER: Cristina Landeta Amber L. Mosley

PROVIDER: MSV000096877 | MassIVE | Thu Jan 16 16:00:00 GMT 2025

SECONDARY ACCESSION(S): PXD059898

REPOSITORIES: MassIVE

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Project description:The emergence of multidrug resistant tuberculosis and the increasing level of resistance urges the search for alternative drugs in treatment. Several neuroleptics, like thioridazine, reveal activity against Mycobacterium tuberculosis. Thioridazine was even successfully applied in compassionate therapy of extensively drug resistant tuberculosis in patients when added to other second and third line antibiotics. The synergistic effects between thioridazine and other anti-tuberculosis drugs is usually assigned to the inhibition of efflux pumps by thioridazine. Using an unbiased proteomic approach, we set out to unravel the molecular mechanism of this potential new anti-tuberculosis component by examining the impact of continuous thioridazine exposure on the proteome of M. tuberculosis. We discovered that under the influence of thioridazine several proteins involved in the maintenance of the cell wall permeability barrier are differentially regulated, while none of the known mycobacterial efflux pumps was differentially regulated on the protein level. By assessing accumulation of fluorescent dyes in M. tuberculosis over time, we demonstrated that long-term drug exposure of M. tuberculosis indeed affected the mycobacterial cell envelope and increased the permeability towards both hydrophilic and hydrophobic compounds. Furthermore, we demonstrated that treatment of M. tuberculosis with thioridazine altered the composition of the plasma membrane. Thioridazine induced an increase in cell envelope permeability, and thereby the enhanced uptake of compounds, this could explain the previously reported synergistic effects between thioridazine and other anti-tuberculosis drugs. Although the hypothesis of higher intercellular drug concentrations by THZ has not changed in this study, the more exact knowledge on its mode of action is a major step forward. This new insight in the molecular mechanism of this anti-tuberculosis compound could facilitate further development of this class of drugs for application in drug therapy of multidrug resistant tuberculosis. In fact, the efficacy of many existing drugs could be improved significantly.

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Disulfide bonds are critical for stabilizing cell division, cell envelope biogenesis, and antibiotic resistance proteins in mycobacteria

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