Design, Synthesis and Evaluation of QuAOCOM-Linked Halogenated Phenazines as Potent Antibacterial and Biofilm-Killing Agents

Bacterial biofilms are surface-attached communities with enriched populations of non-replicating persister cells. As such, biofilms are credited as the underlying cause of chronic and recurring bacterial infections. Unlike free-floating, replicating planktonic bacteria that can acquire resistance to conventional antibiotic treatments, metabolically-dormant biofilm communities exhibit intrinsic tolerance to all classes of antibiotics. To address challenges associated with bacterial biofilms, our lab has identified halogenated phenazine (HP) small molecules that demonstrate outstanding antibacterial and biofilm-killing activities via iron starvation. Here, we report the design, chemical synthesis, and evaluation of a focused series of quinone alkyloxycarbonyloxymethyl(QuAOCOM)-linked HP prodrugs. During these studies, we found QuAOCOM-linked HPs 22 and 27 to demonstrate very good linker stability, rapid processing of the quinone trigger, improved water solubilities, potent antibacterial and biofilm eradication activities, and favorable cytotoxicity profiles. These studies highlight important features related to the design of HP prodrug conjugates which could have a significant impact addressing problems associated with antibiotic-tolerant biofilms.