Anti-virulence approaches and novel peptidomimetics for combating resistant and biofilm associated bacteria

Abstract

Anti-virulence approaches and novel peptidomimetics for combating resistant and biofilm associated bacteria The misuse and overuse of antibiotics has a broad impact on the environment. Antibiotic resistance has become a major threat for modern medical treatment of infectious diseases. There are multiple mechanisms leading to antibiotic resistance such as expression of cell membrane efflux pumps and antibiotic-degrading enzymes. Moreover, bacterial biofilm communities are widely accepted as a major resistance mechanism in infection sites. Biofilms are surface-associated microbial communities consisting of microcolonies embedded in self-produced extracellular polymer substances (EPS). EPS can contribute to cell-cell adhesion and restrict antibiotic penetration. Biofilm cells show much greater resistance to stressful conditions than their free-living counterparts. Conventional treatment strategies could not eradicate biofilm-related infections, such as biofilm infections related to medical implants and chronic wounds. There is a need for developing anti-biofilm therapeutics. Biofilm formation is a dynamic and complicated process which requires cell surface structures (e.g. type IV pili), motility, chemotaxis, subpopulation differentiation, iron signaling and quorum sensing and so on. Targeting these mechanisms might provide alternative strategies to conventional antimicrobial treatment. Microbial cells inside biofilms resemble planktonic cells in stationary phase such as their slow growth rate. Thus development of antimicrobial compounds which are effective against slow growing cells might also be another useful strategy. This Ph.D. project aimed at developing effective treatment strategies against biofilms formed by two model organisms, Pseudomonas aeruginosa and Staphylococcus epidermidis. P.aeruginosa is a gram - negative opportunistic pathogen which causes a variety of severe human infections and diseases, including colonization of the lungs of cystic fibrosis (CF) patients and infection of burns and immunecompromised patients. S.epidermidis is a gram -positive nosocomial pathogen which frequently causes infections associated with implanted foreign materials. In this study, quorum-sensing interfering compounds, iron chelators and efflux pump inhibitors (EPI) have been used for controlling P. aeruginosa biofilms. A series of novel peptidomimetics (a-peptide/ß-peptoid chimeras) have been tested against cells from stationary growth phase and biofilms of S. epidermidis. Structure-activity relationship and cytotoxicity features of these peptidomimetics were explored. Transcriptomic, genomic and adaptive evolution approaches have been applied to address the potential risk of resistance of peptidomimetics, which in turn provide useful information for designing the next generation peptide based anti-biofilm compounds.