Molecular Engineering Approaches against Germs, Spores and Biofilm Formation
Bacterial surface adhesion, colonization and related infections have been major issues plaguing many industrial and biomedical applications. In fact, the very subject has posed engineering challenges and incented scientific questioning for as long as the history of modern day microbiology and materials science themselves. With the rapid advances of molecular engineering in the past few decades, engineers as well as scientists are now equipped with new tools to study and solve these age-old problems. In the wake of these recent developments, the central goal of this thesis is essentially three-fold: first, to expand the existing zwitterionic nonfouling polymer platform for the search of novel and pragmatic solutions to bacterial surface adhesion and subsequent proliferation; second, to adopt a chemical biology approach to understand and potentially combat the extreme survivability of bacterial endospores; and lastly to explore the possible new routes and targets for future anti-virulence small molecules against biofilm formation. This dissertation is thus divided into these three sections accordingly: Traditional zwitterionic polymers have been widely accepted and routinely applied because of their biocompatibility and nonfouling property. However, less recognized are their responsiveness to environmental stimuli, their chemical malleability, their ease to be integrated into more complex systems as well as the biological significance of this polymer structural diversity. It is the intention to the first part of this dissertation to expand our current capacity and understanding of zwitterionic-based materials to cater to more complicated or more specific biomedical scenarios. Four aspects of molecular engineering were presented in this section: (1) first, to exploit the pH responsive property of traditional carboxylbetaine zwitterionic polymers for bacteria detection; (2) one step further, on a monomer level, to design novel hydrolysable zwitterionic molecules that are simultaneously nonfouling and antimicrobial; (3) on a polymeric level, to integrate an antimicrobial zwitterionic derivative portion into wound dressing block copolymers that can undergo both monomer hydrolysis as well as polymer temperature-induced in situ gelation; (4) and finally to investigate how different molecular structures impact zwitterionic polymer performance in complex biological environments, and, in particular, their interactions with bacterial extracellular polysaccharides (EPS). Bacterial endospores are among the most tenacious life forms on earth, and are highly resistant to traditional antibiotic compounds and disinfection procedures. For this reason, in the second part of this thesis, the focus was shifted from normal vegetative bacterial cells to dormant bacterial endospores: first, to unveil the mechanism behind spore extreme survivability by studying dodecylamine (DDA) lethal germination process as a model system; and second, to apply this newly acquired fundamental understanding in the design of new environmentally benign and easily implementable anti-spore strategies. Perhaps the most urgent challenge and threat facing clinical microbiology at the moment is the rapid emergence of antibiotic-resistant strains due to decades of extensive usage of antibiotic drugs. One promising strategy to circumvent this problem of rapid evolution under strong antibiotic selection pressure is the development of so-called "anti-virulence" drugs that seeks to disarm bacteria by limiting their virulent phenotypes instead of directly killing bacteria. The last part of this thesis explore the feasibility of using bacterial osmoprotectant analogues as such anti-virulence metabolites to interfere with glycine betaine homeostasis and potentially impair P.aeruginosa biofilm formation without causing a detrimental effect on planktonic bacterial cells.
- Chemical engineering