Discovery of Antibacterial & Biofilm-Eradicating Agents

Antibiotic resistance and antibiotic tolerance are two distinct biological phenomenon that pose a significant threat to human health worldwide.  Antibiotic resistance results from bacteria acquiring resistance to antibiotic therapies whereas antibiotic tolerance stems from persistent phenotypes (i.e., persister cells living within surface-attached bacterial communities called biofilms).  It should also be noted that our entire arsenal of antibiotics were originally discovered as bacterial growth-inhibiting agents; therefore, non-replicating or slow-growing biofilms have evaded front-running chemotherapies.

Each year in the United States, there are 17 million new biofilm-associated bacterial infections that lead to 550,000 deaths.  Biofilms house metabolically dormant, non-dividing persister cells that are encased within a protective extracellular polymeric matrix of biomolecules and display tolerance to every known class of antibiotic.  Despite the urgent need for clinical agents to effectively kill persistent biofilms, no biofilm-eradicating therapeutic currently exists, thus the development of the first biofilm-eradicating therapeutic agent would be one of the most critical biomedical breakthroughs of the twenty-first century.

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Our lab is interested in identifying new antibacterial agents that operate through unique modes of action to serve as tool molecules to understand complex biological systems and translate our findings into therapeutic agents.  In particular, our group seeks to identify small molecules that are capable of eradicating both planktonic (rapidly dividing, free-swimming) and biofilm (persistent, surface-attached communities) bacteria using a unique blend of synthetic organic chemistry, microbiology and chemical biology.

Halogenated Phenazine Biofilm-Eradicating and Anti-tuberculosis Agents

See some of our recent work describing new halogenated phenazines that kill bacterial biofilms and demonstrate antibacterial activities against the persistent bacterial pathogen Mycobacterium tuberculosis (TB).

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Halogenated Quinoline Biofilm-Eradicating Agents

We have identified several diverse sub-libraries of halogenated quinoline small molecules that display potent antibacterial and biofilm eradication activities.  This biological activity is highly tunable through very practical synthetic methods.

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Select Phytochemicals Potentiate the Antibacterial Activities of Halogenated Quinolines

We have discovered that several phytochemicals, including gallic acid, dramatically potentiate select halogenated quinoline antibacterial agents against a broad spectrum of pathogenic bacteria, including: Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis.  In addition, we found the gallic acid-halogenated quinoline combination to be highly active against several multi-drug resistant strains including multiple clinical isolates.

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PA = Potentiating Agent (Gallic Acid) can be seen increasing the antibacterial activity of halogenated quinolines (compounds 1-3 in the panel above) against Staphylococcus aureus.  Compound 1 is potentiated 11,800-fold with gallic acid, which is non-toxic to S. aureus.