| Small molecules that can attenuate bacterial biofilm formation and virulence factor production by interfering with bacterial chemical communication may provide solutions for the treatment of bacterial infections. Biofilms are a surface attached community of microorganisms that are embedded in an extracellular matrix of polymeric biomolecules. Virulence factors are entities produced by a pathogenic organism, such as bacteria, viruses, and fungi and are most commonly associated with the ability of the pathogen to cause disease. The National Institutes of Health (NIH) estimates that a large fraction of microbial infections that occur in the human body are linked to the formation of biofilms. Biofilms are inherently insensitive to antiseptics and antimicrobials that often exterminate their planktonic counterparts, and are difficult to eradicate from living and non-living surfaces. This work aims to employ small molecules that disrupt bacterial communication to control: the initial attachment of bacteria to a surface (inhibition of biofilm formation), dispersion of a biofilm (removal of preformed biofilm), and the suppression of resistance to common antibiotics. To achieve this aim, molecular scaffolds that have the capacity to disrupt Gram-negative and Gram-positive biofilms via a non-microbicidal mechanism have been generated. Herein the design, synthesis, and biological assessment of two unique classes of nitrogen dense small molecules based on the oroidin and flustramine families (2-aminoimidazoles and pyrroloindoline/indolic alkaloids, respectively) of marine natural products are described for their ability to alter biofilm formation and suppress antibiotic resistance. Library generation and structure activity relationships were constructed to discover lead small molecules that have the ability to reduce biofilm formation, disperse biofilm mass, suppress multi-drug resistance, and interfere with indole signaling pathways. It is the hope that these two classes of natural product derived small molecules will ultimately lead to the discovery of novel antimicrobial agents or therapies. |
