A Modular Synthetic Route Involving N-Aryl-2-nitrosoaniline Intermediates Leads to a New Series of 3-Substituted Halogenated Phenazine Antibacterial Agents

Pathogenic bacteria demonstrate incredible abilities to evade conventional antibiotics through the development of resistance and formation of dormant, surface-attached biofilms. Therefore, agents that target and eradicate planktonic and biofilm bacteria are of significant interest. We explored a new series of halogenated phenazines (HP) through the use of N-aryl-2-nitrosoaniline synthetic intermediates that enabled functionalization of the 3-position of this scaffold. Several HPs demonstrated potent antibacterial and biofilm-killing activities (e.g., HP 29, against methicillin-resistant Staphylococcus aureus: MIC = 0.075 mu M; MBEC = 2.35 mu M), and transcriptional analysis revealed that HPs 3, 28, and 29 induce rapid iron starvation in MRSA biofilms. Several HPs demonstrated excellent activities against Mycobacterium tuberculosis (HP 34, MIC = 0.80 mu M against CDC1551). This work established new SAR insights, and HP 29 demonstrated efficacy in dorsal wound infection models in mice. Encouraged by these findings, we believe that HPs could lead to significant advances in the treatment of challenging infections.

Automated summary

The study introduced a new series of halogenated phenazines (HP) with potent antibacterial and biofilm-killing activities, targeting and eradicating planktonic and biofilm bacteria, showing efficacy against methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis. Transcriptional analysis revealed rapid iron starvation induced by HPs in MRSA biofilms, offering new insights into treating challenging infections._HP 29 demonstrated efficacy in dorsal wound infection models in mice, suggesting HPs could lead to significant advances in infection treatment.