Progress towards a stable cephalosporin-halogenated phenazine conjugate for antibacterial prodrug applications

Xiao, Tao; Liu, Ke; Huigens, Robert W.

doi:10.1016/j.bmcl.2020.127515

Cited by 10 publications

(8 citation statements)

References 31 publications

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“…Next, biochemical studies with a blaC knockout strain suggested that BlaC activity was largely (although perhaps not exclusively) responsible for Pyr release. Finally, microbiological evaluation of the blaC knockout demonstrated increased susceptibility to the Pyr conjugate against replicating organisms and similar to WT activity under non-replicating conditions; potentiation of BLs against Mtb ΔblaC under actively replicating conditions has been demonstrated previously and is likely due to increased inhibition of PBPs, while the retained activity against non-replicating Mtb (for which PBP inhibition is not toxic) suggests the possibility of an alternative release mechanism independent of BLase or PBP activity. , A more expansive study recently reported by the authors, in collaboration with a large number of research organizations, identified additional Pyr cephalosporins with antitubercular activity, further validating this approach and adding to the growing body of evidence supporting BLs as new TB therapeutics. , These recent reports, as well as a few other recent papers exploring BLase fragmentation with fluoroquinolone, phenazine, and pyrazinoic acid conjugates, demonstrate the continued promise of this approach in circumventing limitations such as off-target effects or resistance mechanisms to repurpose known antibiotics for new antibacterial applications (Figure D–F). − Many more examples of BL–antibiotic conjugates can be found in several recent reviews on this subject. − …”

Section: Antibiotics: Lactam Conjugates As Pro- and Co-drugssupporting

confidence: 59%

β-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design

2022

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The discovery of β-lactam (BL) antibiotics in the early 20th century represented a remarkable advancement in human medicine, allowing for the widespread treatment of infectious diseases that had plagued humanity throughout history. Yet, this triumph was followed closely by the emergence of β-lactamase (BLase), a bacterial weapon to destroy BLs. BLase production is a primary mechanism of resistance to BL antibiotics, and the spread of new homologues with expanded hydrolytic activity represents a pressing threat to global health. Nonetheless, researchers have developed strategies that take advantage of this defense mechanism, exploiting BLase activity in the creation of probes, diagnostic tools, and even novel antibiotics selective for resistant organisms. Early discoveries in the 1960s and 1970s demonstrating that certain BLs expel a leaving group upon BLase cleavage have spawned an entire field dedicated to employing this selective release mechanism, termed BLase-mediated fragmentation. Chemical probes have been developed for imaging and studying BLase-expressing organisms in the laboratory and diagnosing BL-resistant infections in the clinic. Perhaps most promising, new antibiotics have been developed that use BLase-mediated fragmentation to selectively release cytotoxic chemical "warheads" at the site of infection, reducing offtarget effects and allowing for the repurposing of putative antibiotics against resistant organisms. This Review will provide some historical background to the emergence of this field and highlight some exciting recent reports that demonstrate the promise of this unique release mechanism.

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Section: Antibiotics: Lactam Conjugates As Pro- and Co-drugssupporting

confidence: 59%

β-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design

2022

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“…This HP prodrug approach offers several advantages, which include (1) enhanced physicochemical properties (i.e., water solubility), (2) mitigation of off-target metal binding that could lead to toxicity (HP prodrugs are unable to bind iron), (3) prevention of rapid phenol conjugation/metabolism, and (4) improved targeting through bacteria-specific release of the active HP/HA agent. HP-focused prodrug efforts are underway, ,,− and developments related to the new analogues described herein will be reported in due course.…”

Section: Resultsmentioning

confidence: 99%

Modular Synthetic Routes to Fluorine-Containing Halogenated Phenazine and Acridine Agents That Induce Rapid Iron Starvation in Methicillin-Resistant Staphylococcus aureus Biofilms

et al. 2022

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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.

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“…13 3.2.1.9. 6-Bromo-3-chloro-1-methoxyphenazine (56). Yield: 61%; 183 mg was isolated as a yellow solid.…”

Section: Methodsmentioning

confidence: 99%

“…Active HPs identified during these studies are ideal candidates for prodrug development through functionalization of the 1-hydroxyl group aimed to enhance physicochemical properties, prevent rapid metabolism (phenol conjugation), mitigate off-target metal binding that could lead to toxicity, and release via bacteria-specific mechanisms. 37,38,56,57 Prodrug efforts related to new HP scaffolds from this study are underway, and findings will be reported in due course.…”

Section: Introductionmentioning

confidence: 94%

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

et al. 2021

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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-2nitrosoaniline 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 μM; MBEC = 2.35 μM), 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 μM 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.

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Progress towards a stable cephalosporin-halogenated phenazine conjugate for antibacterial prodrug applications

Cited by 10 publications

References 31 publications

β-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design

β-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design

Modular Synthetic Routes to Fluorine-Containing Halogenated Phenazine and Acridine Agents That Induce Rapid Iron Starvation in Methicillin-Resistant Staphylococcus aureus Biofilms

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

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