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This study reports on the design and engineering of biohybrid microswimmers exploiting a thiol-mediated self-immolative antibiotic release strategy. The design features a covalent attachment of a vancomycin conjugate via a disulfide-based linker to the surface of the microalgae Chlamydomonas reinhardtii. The antibiotic release from the surface of these biohybrids was triggered by the addition of a thiol-based reducing agent, and, subsequently, the inhibition of bacterial growth was observed for Bacillus subtilis and Staphylococcus aureus. These engineered microbots represent the first example of a microalgae-based drug delivery system with a thiol-mediated, reductive release of an antibiotic drug.

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Due to a steady increase in microbial resistance, there is a need to increase the effectiveness of antibiotic performance by involving additional mechanisms of their penetration or retention for their better action. Cephalosporins are a successful group of antibiotics to combat pathogenic microorganisms, including drug-resistant strains. In this study, we investigated the effect of newly synthesized cephalosporin derivatives with cyclic disulfide modifications against several Gram-positive and Gram-negative strains as well as against biofilm formation. The incorporation of asparagusic acid was found to be effective in improving the activity of the drug against Gram-negative strains compared to the all carbon-control compounds. Furthermore, we could demonstrate the successful reduction of biofilm formation for Staphylococcus aureus and Pseudomonas aeruginosa at similar concentrations as obtained against planktonic cells. We propose that the incorporation of cyclic disulfides is one additional strategy to improve antibiotic activity and to combat bacterial infections.

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Antibiotic-resistant and biofilm-associated infections constitute a rapidly growing issue. Use of the last-resort antibiotic vancomycin is under threat due to the increasing appearance of vancomycin-resistant bacteria as well as the formation of biofilms. Herein, we report a series of novel vancomycin derivatives carrying thiol- and disulfide-containing moieties. The new compounds exhibited enhanced antibacterial activity against a broad range of bacterial strains, including vancomycin-resistant microbes and Gram-negative bacteria. Moreover, all obtained derivatives demonstrated improved antibiofilm formation activity against VanB-resistant Enterococcus compared to vancomycin. This work establishes a promising strategy for combating drug-resistant bacterial infections or disrupting biofilm formation and advances the knowledge on the structural optimization of antibiotics with sulfur-containing modifications.

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Biohybrid microswimmers exploit the natural abilities of motile microorganisms e.g. in releasing cargo on-demand. However, using such engineered swarms to release antibiotics addressing bacterial infections has not yet been realized. Herein, a design strategy for biohybrid microswimmers is reported, which features the covalent attachment of antibiotics with a photo-cleavable linker to the algae Chlamydomonas reinhardtii via two synthetic steps. This surface engineering does not rely on genetic manipulations, proceeds with high efficiency, and retains the viability or phototaxis of microalgae. Two different antibiotics have been separately utilized, which result in activity against both gram-positive and gram-negative strains. Guiding the biohybrid microswimmers by an external beacon, and on-demand delivery of the drugs by light with high spatial and temporal control, allowed for strong inhibition of bacterial growth. This efficient strategy could potentially allow for the selective treatment of bacterial infections by engineered algal microrobots with high precision in space and time. STATEMENT OF SIGNIFICANCE: Biological swimmers with innate sensing and actuation capabilities and integrated components have been widely investigated to create autonomous microsystems. The use of natural swimmers as cargo delivery systems presents an alternative strategy to transport therapeutics to the required locations with the difficult access by traditional strategies. Although the transfer of various therapeutic cargo has shown promising results, the utilization of microswimmers for the delivery of antimicrobials was barely covered. Therefore, we present biohybrid microalga-powered swimmers designed and engineered to carry antibiotic cargo against both Gram-positive and Gram-negative bacteria. Guided by an external beacon, these microhybrids deliver the antibiotic payload to the site of bacterial infection, with high spatial and temporal precision, released on-demand by an external trigger to inhibit bacterial growth.

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The spatial and temporal control of bioactivity of small molecules by light (photopharmacology) constitutes a promising approach for study of biological processes and ultimately for the treatment of diseases. In this study, we investigated two different "caged" antibiotic classes that can undergo remote activation with UV-light at λ = 365 nm, via the conjugation of deactivating and photocleavable units through a short synthetic sequence. The two widely used antibiotics vancomycin and cephalosporin were thus enhanced in their performance by rendering them photoresponsive and thereby suppressing undesired off-site activity. The antimicrobial activity against Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 29213, S. aureus ATCC 43300 (MRSA), Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 could be spatiotemporally controlled with light. Both molecular series displayed a good activity window. The vancomycin derivative displayed excellent values against Gram-positive strains after uncaging, and the next-generation caged cephalosporin derivative achieved good and broad activity against both Gram-positive and Gram-negative strains after photorelease.

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New strategies to efficiently treat bacterial infections are crucial to circumvent the increase of resistant strains and to mitigate side effects during treatment. Skin and soft tissue infections represent one of the areas suffering the most from these resistant strains. We developed a new drug delivery system composed of the green algae, Chlamydomonas reinhardtii, which is generally recognized as safe, to target specifically skin diseases. A two-step functionalization strategy was used to chemically modify the algae with the antibiotic vancomycin. Chlamydomonas reinhardtii was found to mask vancomycin and the insertion of a photocleavable linker was used for the release of the antibiotic. This living drug carrier was evaluated in presence of Bacillus subtilis and, only upon UVA1-mediated release, growth inhibition of bacteria was observed. These results represent one of the first examples of a living organism used as a drug delivery system for the release of an antibiotic by UVA1-irradiation.

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