| A biofilm is defined as a sessile, surface accreted colony of microorganisms that surrounds itself by a protective, self-produced extracellular polymeric substance. In the biofilm state, infectious pathogens such as bacteria and fungus are found to be highly resistant to antimicrobial therapy. Due to their durable nature, biofilm related infections often become chronic and untreatable. This is especially problematic when infectious biofilms form on the surfaces of indwelling medical devices such as urinary catheters, pacemakers, heart valves or orthopedic prostheses, because the only medically practiced means of treating such an infection is through surgical removal of the device. Aside from synthetic surfaces, biofilms also can also form on human tissues such as the case of Pseudomonas aeruginosa biofilms which are found inside the lungs of cystic fibrosis patients. This is the major cause of mortality for these patients since these biofilm-attached surfaces cannot be removed, resulting in unrelenting infections. Impacted with the rapid dissemination of antimicrobial resistance genes and the dearth of emerging antibiotics into the biomedical community, biofilm related infections are becoming increasingly difficult, if not impossible, to treat. Due to the growing threat, the biomedical community has become increasingly motivated to develop methods in which to treat these multidrug resistant biofilm infections. In this vein, this body of work focuses on the design, synthesis and biological testing of marine alkaloid natural product based small molecule libraries for antibiofilm, antibiotic and antibiotic resensitization activities. Multiple classes of compounds have been synthesized and assayed herein that are shown to exhibit unique structural activity relationships among bacterial and fungal pathogens. Furthermore, to assess possible therapeutic value of lead compounds, mammalian red blood cell toxicity analysis has been examined in which these compounds have been found to be non-toxic at active concentrations. |
