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Discovering and Developing Novel Antibiotics: Following Nature's Leads

The ability to effectively treat infections makes possible the practice of modern medicine. One of the most ominous issues in healthcare on the horizon is the rise of antimicrobial resistance. Resistance has rendered many antimicrobials ineffective.  Failure to effectively treat pathogens can have ramifications beyond infectious diseases.  Nature is a great starting point for the discovery and development of antimicrobial therapeutics.  
First, many successful antibiotics are derivatives of natural products. I will present data from a team of scientists at Genentech who exploited insights from natural resistance, structural elucidations and medicinal chemistry to optimize a novel class of antibiotic with potent, broad-spectrum Gram-negative activity from the arylomycin class of natural products that had weak activity and limited spectrum.  These molecules are bactericidal against contemporary MDR Gram-negative clinical isolates in vitro and in multiple in vivo infection models and are poised to be developed in the clinic to address the growing threat of MDR Gram-negative infections.  Nature seems to prefer using macrocyclic compounds (a chemical space that is poorly represented in small molecule screening libraries) as antibiotics.  I will discuss the potential of DNA-based in vitro translation methodologies to enable query into a larger chemical space to discover novel macrocycles against microbial targets.  
Second, the use of antibodies to treat infection predates the discovery of antibiotics and are being exploited as therapeutics for infectious diseases, for example a monoclonal antibody bezlotoxumab that targets C. difficile toxin B for recurrent C. difficile infection.  However, no antibody with bactericidal activity against bacterial pathogens is currently in clinical development.  I will discuss challenges in discovering and developing mAbs as therapeutics.