Structure-Activity Relationships of a Diverse Class of Halogenated Phenazines That Targets Persistent, Antibiotic-Tolerant Bacterial Biofilms and Mycobacterium tuberculosis

Persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. Here, we describe the structure activity relationships of a series of halogenated phenazines (HP) inspired by 2-bromo-l-hydroxyphenazine 1. Using multiple synthetic pathways, we probed diverse substitutions of the HP scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacterial eradication profiles. Halogenated phenazine 14 proved to be the most potent biofilm-eradicating agent (>= 99.9% persister cell killing) against MRSA (MBEC < 10 mu M), MRSE (MBEC = 2.35 mu M), and VRE (MBEC = 0.20 mu M) biofilms while 11 and 12 demonstrated excellent antibacterial activity against M. tuberculosis (MIC = 3.13 mu M). Unlike antimicrobial peptide mimics that eradicate biofilms through the general lysing of membranes,}IN do not lyse red blood cells. HPs are promising agents that effectively target persistent bacteria while demonstrating negligible toxicity against mammalian cells.