In our internal antibacterial program, we have discovered a variety of novel compounds that show promising inhibition of bacterial biofilms and that are synthetically accessible.  Our research to date indicates that these compounds we have identified as biofilm inhibitors appear to prevent the formation or maintenance of a protective coating produced by bacteria that increase the bacteria’s resistance to immune responses and antibiotics and enable their attachment to surfaces including human cells, medical devices, and teeth.  Our lead compounds have demonstrated broad-spectrum biofilm inhibition against Streptococci spp., Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa.  Moreover, these compounds have demonstrated synergistic effects with antibiotics in bioreactors mimicking the resistant biofilms observed in chronic infections.

These novel compounds specifically target biofilms, bacteria embedded in a structural matrix.  The discovery of biofilms is rather recent, but now, the presence of biofilms is recognized as ubiquitous:  mildew festering in bathroom grout, plaque film accumulating on teeth and river rocks covered in slime.

The process by which free-floating bacteria settle into a complex community of biofilm-embedded bacteria consists of three stages.  First, individual bacteria cells attach to a surface and begin to secrete a polysaccharide matrix, a slimy layer that encases the bacteria.  Second, the bacteria cells grow into a community with channels that provide nutrients and discard waste.  Third, the community thrives in proportion to its efficiency in intercellular signaling and the degree of protection provided by the polysaccharide matrix.

Within biofilms, bacteria are able to resist antibiotics at concentrations ranging from 1 to 1.5 thousand times higher than the concentrations used in conventional antibiotic therapy.  Similarly, bacteria surrounded by biofims are rarely resolved by immune defense mechanisms.  As a consequence, biofilms are the source of serious and chronic infections, including urinary tract infections, lung infections, sinus infections, ear infections, acne, chronic wounds, and periodontitis. Biofilms, by virtue of their structural matrix, adhere to the inert surfaces of implanted medical devices, such as central venous catheters, endotracheal tubes, mechanical heart valves, pacemakers and prosthetic joints.  In the United States, more than 7 million patients per year are recipients of implanted devices; approximately one-half of these patients develop infections that current antibiotics cannot treat effectively.

With increasing emergence of antibiotic-resistant bacteria, biofilm-related chronic infections represent a highly complex and escalating medical problem.  Inhibitors must be developed that specifically target the biological mechanisms that provide bacteria protection from antibiotics and the immune system.  Historically, compounds isolated from plants have been a source of powerful antimicrobials.  Sequoia, by increasing the rate of discovery of novel compounds from plants, is uniquely positioned to develop biofilm-inhibiting drugs.

 For more information about Sequoia's research with biofilms, click here.