Biology subjects

Mejia-Santana, A.

Publications and source records attributed to Mejia-Santana, A..

2 recordsLinked to original sources

bioRxiv2025

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

Mycobacteria, including Mycobacterium tuberculosis--the etiological agent of tuberculosis--have a unique cell envelope critical for their survival and resistance. The cell envelopes assembly and maintenance influence permeability, making it a key target against multidrug-resistant strains. Disulfide bond (DSB) 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 cysteine profiling 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. Furthermore, chemical inhibition of VKOR results in phenotypes similar to those of {Delta}vkor. Thus, targeting DsbA-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.

microbiology↗

bioRxiv2024

Warfarin analogs target disulfide bond-forming enzymes and suggest a residue important for quinone and coumarin binding

Disulfide bond formation has a central role in protein folding of both eukaryotes and prokaryotes. DsbB and VKOR enzymes catalyze the oxidation of the oxidoreductase partner and the formation of de novo disulfide bonds using quinone as cofactor. We have used E. coli and a family of warfarin analogs to study de novo disulfide bond formation. We found that human VKORc1 can function in E. coli by removing two positive residues, allowing the search for novel anticoagulants. One analog was capable of inhibiting both bacterial DsbB and VKOR, and a second one antagonized only the mammalian enzymes. We identified the two amino acid residues responsible for binding. One of these is also essential for quinone binding in both DsbB and VKOR. Our studies highlight a conserved role of this residue in de novo disulfide-generating enzymes and enable the design of novel anticoagulants or antibacterials using coumarin as a scaffold.

microbiology↗