Probing for Thiol‐Mediated Uptake into Bacteria

Abstract

Cellular uptake mediated by cyclic oligochalcogenides (COCs) is emerging as a conceptually innovative method to penetrate mammalian cells. Their mode of action is based on dynamic covalent oligochalcogenide exchange with cellular thiols. To test thiol‐mediated uptake in bacteria, five antibiotics have been equipped with up to three different COCs: One diselenolane and two dithiolanes. We found that the COCs do not activate antibiotics in Gram‐negative bacteria. In Gram‐positive bacteria, the COCs inactivate antibiotics that act in the cytoplasm and reduce the activity of antibiotics that act on the cell surface. These results indicate that thiol‐mediated uptake operates in neither of the membranes of bacteria. COCs are likely to exchange with thiols on the inner, maybe also on the outer membrane, but do not move on. Concerning mammalian cells, the absence of a COC‐mediated uptake into bacteria observed in this study disfavors trivial mechanisms, such as passive diffusion, and supports the existence of more sophisticated, so far poorly understood uptake pathways.

Design of Oligourea-Based Foldamers with Antibacterial and Antifungal Activities

“…This may suggest that, in aqueous medium at neutral or basic pH, the hydrophobic faces of the two helical segments of DIM-3 could pack together sufficiently tightly through hydrophobic effect to mask the hydrophobic face of the helix for optimal interaction with the bacterial membrane [ 28 ]. Another explanation for the reduced antibacterial activity of DIM-3 could be the presence of the disulfide bridge itself, in agreement with the recent results of Matile et al, who found that thiol-mediated uptake is inefficient in bacteria and that the addition of thiol reactive groups to antibiotics may actually reduce their activity [ 39 ].…”

Thiol and Disulfide Containing Vancomycin Derivatives Against Bacterial Resistance and Biofilm Formation

“…In earlier work by the group of Matile, it was demonstrated that the introduction of cyclic disulfides or selenides into vancomycin structure leads to either no improvement in activity or its slight loss when tested against Gram-positive B. subtilis . 43 Moreover, the Gram-negative strain did not show any sensitivity to the antibiotic after its modification. However, in our work, we showed significant increase of the antibiotic activity against several sensitive and resistant strains including Gram-negative M. catarrhalis after the incorporation of either cyclic disulfides or other sulfur-containing linkers into vancomycin structure.…”

“…However, utilizing thiol-mediated uptake in bacteria was rarely investigated, and the results obtained have been mixed so far. 40 Additionally, to growing resistance, about 80% of all chronic infections are associated with an increased survive ability of a causative pathogen in a formed biofilm. [41][42][43] Among them, Grampositive cocci are well established bacteria related to biofilm infections.…”

“…However, utilizing thiol-mediated uptake in bacteria was rarely investigated, and the results obtained have been mixed so far. 43…”

“…Lipoic acid derivatives ( 1a-c ) have been chosen along the line of successful eukaryotic, thiol-mediated uptake systems, 50 which have earlier also been evaluated with mixed success against bacteria. 43 Endolipidic disulfides ( 2a-c ) were selected to increase lipophilicity, which should also positively influence residence time and potentially involve other mechanisms of actions, such as disruption of cell-wall integrity and inhibition of transglycosylases. 51 Terminal thiols were selected, both with internal disulfides ( 3a/3b ) and without ( 4a-d ), which would be most accessible to any bacterial counterpart.…”