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Bioadhesives are essential for tissue adhesion and regeneration. Optimal bioadhesive should possess elasticity, robust adhesion capabilities in wet environments, and a cytocompatible scaffold for cell regeneration. Current options like cyanoacrylates and fibrin glues fail in these aspects due to cell toxicity and poor moisture adhesion, prompting the need for new materials that reconcile cytocompatibility with robust adhesion. These limitations by available commercial bioadhesives, demand the development of new adhesive biomaterials that combine cytocompatibility with strong adhesion. Marine organisms such as mussels secrete proteins that adhere effectively even underwater, but the adhesion mechanisms remain partly elusive. These proteins' adhesion strength is largely attributed to catechol side chains of L-Dopa, which can form various surface interactions, including hydrogen bonding and metal coordination. Commercial use of natural adhesive proteins is time- and labor-demanding, and uneconomical, as it takes thousands of mussel specimens to extract just one gram of adhesive proteins. In addition, low expression yield, low purification yield, and high levels of post-purification insolubility, restrict the production of recombinant foot protein types in Escherichia coli. To overcome these issues and inspired by intrinsically disordered domains of tropoelastin, the soluble precursor of elastin, elastin-like polypeptides (ELPs) consist of repeated sequences of the pentapeptide motif “VPGXG” (with “X” representing any amino acids except proline), emerge as promising synthetic alternatives. These stimuli-responsive adhesives exhibit a reversible phase transition regulated by temperature, making them suitable for applications such as drug delivery and wound healing. Their lower critical solution temperature (LCST) can be genetically adjusted to just below human body temperature, offering versatility for medical use. The bioadhesive efficacy of ELPs is linked to Dopa, cruc

Tetracyclines and -lactam antibiotics are affected by multiple bacterial resistance mechanisms. One of the major resistance pathways is the alteration of the outer membrane and porin channels that prevent the entry of antibiotics into the periplasmic space. To address this issue, iron-chelators have been attached to -lactam antibiotics to facilitate entry through a siderophore-mediated uptake system and by-pass porin channels such as cefiderocol. Alternatively, potent membrane permeabilizing agents are being developed that can disrupt the outer membrane to increase antibiotics influx, such as tobramycin-based hybrids. Several reports also suggests that the nonselective metal ion binding of tetracycline affects interactions with the target-site. Iron-chelator like deferiprone has been shown to be useful in addressing this non-selectivity by facilitating the binding of tetracycline to the target. Therefore, we hypothesize that we can utilize both properties in a hybrid molecule, i.e., membrane permeabilization and iron-chelation, to overcome tetracycline resistance against Gram-negative bacteria. This M.Sc. thesis focuses on the development of novel hybrids of tobramycin-deferiprone. Total six hybrids and two control compounds were synthesized and tested against Gram-negative bacteria, especially; Pseudomonas aeruginosa, for determining antibacterial properties. Checkerboard assays were also conducted with a panel of antibiotics to determine the synergistic relationship with these hybrids. The results strengthen our hypothesis of linking tobramycin and deferiprone to achieve tetracycline potentiation because the single drug entities (control compounds) are not able to achieve comparable results like our hybrid molecules. Probable mechanism of action could be the internalization effect that renders an increased tetracycline accumulation, allowing it to illicit antimicrobial action with minimal concentration.

Currently, urea is widely believed to unfold proteins by increasing the solubility of the amide backbone through direct interactions rather than through global changes in solvent water structure. Urea is thought to enhance hydrogen bonding or van der Waals interactions, thereby increasing the solubility of the amide backbone. However, there are few experimental data to confirm any of these proposed mechanisms. In this work, we first investigated the effects of urea addition on the hydrogen bonding network of water by measuring how it perturbs the fluorescence spectra of the 1-aminonaphthalene (1-AN) and 1-dimethylaminonaphthalene (1-DMAN) molecules involved in hydrogen bonding. In both cases, the fluorescence spectra of the two molecules show that the hydrogen bonding properties of the solvent are minimally affected by the addition of urea from the solute point of view. We have also studied the effects of urea addition on intra-molecular hydrogen bonding as represented by the carboxylate-hydroxyl bond in salicylic acid. Our measurements show that the addition of urea has no effect on the strength of the intra-molecular hydrogen bonds. Finally, we investigate how the addition of urea perturbs the solvation energy of amide moieties in water by comparing the urea-induced changes in the solubility of acetaminophen and 4-tertbutylphenol. Our measurements show that the addition of urea has no appreciable effect on the hydrogen bonding interactions between amide and solvent. Rather, we show that the increase in amide solvation enthalpy correlates linearly with the change in solvent packing density. This confirms the enhanced van der Waals interactions between the solvent and dissolved amide groups in binary urea-water mixtures (relative to pure water). The results of work presented here clearly confirm the theoretical calculations that identify an increase in van der Waals interactions between solvent and amide as the main mechanism for protein denaturation.