Inhibition and Dispersion of Biofilms: Targeting Bacterial Response Regulators to Resensitize Multidrug Resistant Bacteria to Antibiotics

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Biofilms provide cells with protection against numerous physical and chemical assaults. Bacteria utilize biofilms to avoid antibiotics, leaving the bacteria resistant to antibiotic treatments. The rise of antibiotic resistance and lack of new viable treatments threaten to usher in a post‐antibiotic era if new approaches towards drug development are not made. Many of the currently available antibiotics target a narrow spectrum of metabolic processes required for cellular growth. These traditional approaches no longer offer long‐term protection due to the acquisition rate of resistance; new mechanisms must be pursued. One such mechanism is through the two‐component systems (TCSs) used in bacterial communication. TCSs allow the cell to detect and respond to changes in its environment and are used to trigger quorum sensing and virulence factors. Drugs that target the TCS signaling process could inhibit pathogenic behavior, making them a potent new approach that has not yet been exploited. The TCS response regulator BfmR from Acinetobacter baumannii is the master controller of biofilm formation, making BfmR an attractive drug target. BfmR is targeted by 2‐aminoimidazoles (2AIs), compounds that inhibit and disperse biofilms in Gram‐negative and Gram‐positive bacteria. This work focuses on the interactions between 2AI based compounds and the response regulators BfmR and PmrA/QseB, from Fancisella tularensis, which also regulates biofilm development. Understanding the impact of 2AIs on response regulators and their mechanism of interaction will lead to the development of more potent inhibitors.