During
infection, bacteria use an arsenal of resistance mechanisms
to negate antibiotic therapies. In addition, pathogenic bacteria form
surface-attached biofilms bearing enriched populations of metabolically
dormant persister cells. Bacteria develop resistance in response to
antibiotic insults; however, nonreplicating biofilms are innately
tolerant to all classes of antibiotics. As such, molecules that can
eradicate antibiotic-resistant and antibiotic-tolerant bacteria are
of importance. Here, we report modular synthetic routes to fluorine-containing
halogenated phenazine (HP) and halogenated acridine (HA) agents with
potent antibacterial and biofilm-killing activities. Nine fluorinated
phenazines were rapidly accessed through a synthetic strategy involving
(1) oxidation of fluorinated anilines to azobenzene intermediates,
(2) SNAr with 2-methoxyaniline, and (3) cyclization to
phenazines upon treatment with trifluoroacetic acid. Five structurally
related acridine heterocycles were synthesized using SNAr and Buchwald–Hartwig approaches. From this focused collection,
phenazines 5g, 5h, 5i, and
acridine 9c demonstrated potent antibacterial activities
against Gram-positive pathogens (MIC = 0.04–0.78 μM).
Additionally, 5g and 9c eradicated Staphylococcus aureus, Staphylococcus
epidermidis and Enterococcus faecalis biofilms with excellent potency (5g, MBEC = 4.69–6.25
μM; 9c, MBEC = 4.69–50 μM). Using
real-time quantitative polymerase chain reaction (RT-qPCR), 5g, 5h, 5i, and 9c rapidly
induce the transcription of iron uptake biomarkers isdB and sbnC in methicillin-resistant S. aureus (MRSA) biofilms, and we conclude that these
agents operate through iron starvation. Overall, fluorinated phenazine
and acridine agents could lead to ground-breaking advances in the
treatment of challenging bacterial infections.
Antibiotic-resistant infections present significant challenges to patients. As a result, there is considerable need for new antibacterial therapies that eradicate pathogenic bacteria through non-conventional mechanisms. Our group has identified a...
Pathogenic bacteria have devastating impacts on human health as a result of acquired antibiotic resistance and innate tolerance. Every class of our current antibiotic arsenal was initially discovered as growth-inhibiting agents that target actively replicating (individual, free-floating) planktonic bacteria. Bacteria are notorious for utilizing a diversity of resistance mechanisms to overcome the action of conventional antibiotic therapies and forming surface-attached biofilm communities enriched in (nonreplicating) persister cells. To address problems associated with pathogenic bacteria, our group is developing halogenated phenazine (HP) molecules that demonstrate potent antibacterial and biofilm-eradicating activities through a unique iron starvation mode of action. In this study, we designed, synthesized, and investigated a focused collection of carbonate-linked HP prodrugs bearing a quinone trigger to target the reductive cytoplasm of bacteria for bioactivation and subsequent HP release. The quinone moiety also contains a polyethylene glycol group, which dramatically enhances the water-solubility properties of the HP-quinone prodrugs reported herein. We found carbonate-linked HPquinone prodrugs 11, 21−23 to demonstrate good linker stability, rapid release of the active HP warhead following dithiothreitol (reductive) treatment, and potent antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis, and Enterococcus faecalis. In addition, HP-quinone prodrug 21 induced rapid iron starvation in MRSA and S. epidermidis biofilms, illustrating prodrug action within these surface-attached communities. Overall, we are highly encouraged by these findings and believe that HP prodrugs have the potential to address antibiotic resistant and tolerant bacterial infections.
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