Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N... Show moreBrevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assays and in vivo infection models. Show less
Conjugation of drugs to polymers is a widely used approach to gain control over the release of therapeutics. In this contribution, salicylic acid, a multipurpose model drug, is conjugated to the... Show moreConjugation of drugs to polymers is a widely used approach to gain control over the release of therapeutics. In this contribution, salicylic acid, a multipurpose model drug, is conjugated to the biocompatible poly(2-ethyl-2-oxazoline) (PEtOx). The drug is attached to the side chains of a polymer carrier through a hydrolytically cleavable ester linker, via a sequential postpolymerization modification. The chemical modulation of this ester, i.e., by primary or secondary alcohols, is demonstrated to greatly influence the ester hydrolysis rate. This crucial parameter allows us to tune the in vitro kinetics of the sustained drug release for periods exceeding a month in phosphate-buffered saline (PBS). The synthetic accessibility of the cleavable linker, together with the modularity of the drug release rate offered by this approach, highlights the utility of this class of polymers in the field of long-lasting drug delivery systems for persistent and chronic disease treatment. Show less
The research in this thesis is focused on tomographic reconstruction based on two imaging modalities in electron microscopy. The first modality is high angle annular dark field scanning... Show moreThe research in this thesis is focused on tomographic reconstruction based on two imaging modalities in electron microscopy. The first modality is high angle annular dark field scanning transmission microscopy (HAADF-STEM), and the second modality is energy-dispersive X-ray spectroscopy (EDS). In this Ph.D. thesis, we propose several approaches to pave the way for HAADF- STEM + EDS tomography: (1) the HAADF-EDS bimodal tomographic reconstruction technique, which is based on jointly modeling the consistency of the two imaging modalities; (2) TNV-regularized joined reconstruction which allows to incorporate the prior knowledge that common edges exist in the reconstructions from HAADF and EDS data respectively; (3) a set of algorithmic recipes to tailor various reconstruction algorithms for given experimental conditions and sample properties; (4) an algorithm for automatically correcting the nonlinear damping effects in HAADF-STEM tomographic data. Show less
