Design, Synthesis and Biological Evaluation of a Halogenated Phenazine-erythromycin Conjugate Prodrug for Antibacterial Applications

Overview

Journal Org Biomol Chem

Publisher Royal Society of Chemistry

Specialties Biochemistry
Chemistry

Date 2021 Feb 1

PMID 33521803

Citations 12

Authors

Hongfen Yang

Ke Liu

Shouguang Jin

Robert W Huigens Iii

Affiliations

Soon will be listed here.

Abstract

There is a significant need for new antibacterial agents as pathogenic bacteria continue to threaten human health through the acquisition of resistance and tolerance towards existing antibiotics. Over the last several years, our group has been developing a novel series of halogenated phenazines that demonstrate potent antibacterial and biofilm eradication activities against critical Gram-positive pathogens, including: Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium. Here, we report the design, chemical synthesis and initial biological assessment of a halogenated phenazine-erythromycin conjugate prodrug 5 aimed at enhancing the translational potential for halogenated phenazines as a treatment of bacterial infections.

Citing Articles

Recent Advances in Phenazine Natural Products: Chemical Structures and Biological Activities.

Huang W, Wan Y, Zhang S, Wang C, Zhang Z, Su H Molecules. 2024; 29(19).

PMID: 39407699 PMC: 11477647. DOI: 10.3390/molecules29194771.

Design, synthesis and evaluation of halogenated phenazine antibacterial prodrugs targeting nitroreductase enzymes for activation.

Liu K, Xiao T, Yang H, Chen M, Gao Q, Brummel B RSC Med Chem. 2023; 14(8):1472-1481.

PMID: 37593580 PMC: 10429720. DOI: 10.1039/d3md00204g.

Design, Synthesis, and Evaluation of Carbonate-Linked Halogenated Phenazine-Quinone Prodrugs with Improved Water-Solubility and Potent Antibacterial Profiles.

Xiao T, Liu K, Gao Q, Chen M, Kim Y, Jin S ACS Infect Dis. 2023; 9(4):899-915.

PMID: 36867688 PMC: 10551733. DOI: 10.1021/acsinfecdis.2c00558.

Design, Synthesis and Biological Evaluation of Conjugates of 3--Descladinose-azithromycin and Nucleobases against rRNA A2058G- or A2059G-Mutated Strains.

Lian X, Liu W, Fan B, Yu M, Liang J Molecules. 2023; 28(3).

PMID: 36770992 PMC: 9920417. DOI: 10.3390/molecules28031327.

Adenosine triphosphate-activated prodrug system for on-demand bacterial inactivation and wound disinfection.

Weng Y, Chen H, Chen X, Yang H, Chen C, Tan H Nat Commun. 2022; 13(1):4712.

PMID: 35953495 PMC: 9372092. DOI: 10.1038/s41467-022-32453-3.

References

Katz L, Ashley G . Translation and protein synthesis: macrolides. Chem Rev. 2005; 105(2):499-528. DOI: 10.1021/cr030107f. View

Garrison A, Abouelhassan Y, Norwood 4th V, Kallifidas D, Bai F, Nguyen M . Structure-Activity Relationships of a Diverse Class of Halogenated Phenazines That Targets Persistent, Antibiotic-Tolerant Bacterial Biofilms and Mycobacterium tuberculosis. J Med Chem. 2016; 59(8):3808-25. DOI: 10.1021/acs.jmedchem.5b02004. View

Tian J, Han X, Lv W, Li Y, Wang H, Fan B . Design, synthesis and structure-bactericidal activity relationships of novel 9-oxime ketolides and reductive epimers of acylides. Bioorg Med Chem Lett. 2017; 27(7):1513-1524. DOI: 10.1016/j.bmcl.2017.02.041. View

Abouelhassan Y, Zhang Y, Jin S, Huigens 3rd R . Transcript Profiling of MRSA Biofilms Treated with a Halogenated Phenazine Eradicating Agent: A Platform for Defining Cellular Targets and Pathways Critical to Biofilm Survival. Angew Chem Int Ed Engl. 2018; 57(47):15523-15528. PMC: 6407420. DOI: 10.1002/anie.201809785. View

Wood T . Combatting bacterial persister cells. Biotechnol Bioeng. 2015; 113(3):476-83. DOI: 10.1002/bit.25721. View

Borrero N, Bai F, Perez C, Duong B, Rocca J, Jin S . Phenazine antibiotic inspired discovery of potent bromophenazine antibacterial agents against Staphylococcus aureus and Staphylococcus epidermidis. Org Biomol Chem. 2014; 12(6):881-6. DOI: 10.1039/c3ob42416b. View

Fisher J, Mobashery S . Endless Resistance. Endless Antibiotics?. Medchemcomm. 2016; 7(1):37-49. PMC: 5060946. DOI: 10.1039/C5MD00394F. View

Brown E, Wright G . Antibacterial drug discovery in the resistance era. Nature. 2016; 529(7586):336-43. DOI: 10.1038/nature17042. View

Abouelhassan Y, Garrison A, Yang H, Chavez-Riveros A, Burch G, Huigens 3rd R . Recent Progress in Natural-Product-Inspired Programs Aimed To Address Antibiotic Resistance and Tolerance. J Med Chem. 2019; 62(17):7618-7642. PMC: 6742553. DOI: 10.1021/acs.jmedchem.9b00370. View

10.

Yang H, Abouelhassan Y, Burch G, Kallifidas D, Huang G, Yousaf H . A Highly Potent Class of Halogenated Phenazine Antibacterial and Biofilm-Eradicating Agents Accessed Through a Modular Wohl-Aue Synthesis. Sci Rep. 2017; 7(1):2003. PMC: 5435703. DOI: 10.1038/s41598-017-01045-3. View

11.

Cochrane S, Li X, He S, Yu M, Wu M, Vederas J . Synthesis of Tridecaptin-Antibiotic Conjugates with in Vivo Activity against Gram-Negative Bacteria. J Med Chem. 2015; 58(24):9779-85. DOI: 10.1021/acs.jmedchem.5b01578. View

12.

Garrison A, Abouelhassan Y, Kallifidas D, Tan H, Kim Y, Jin S . An Efficient Buchwald-Hartwig/Reductive Cyclization for the Scaffold Diversification of Halogenated Phenazines: Potent Antibacterial Targeting, Biofilm Eradication, and Prodrug Exploration. J Med Chem. 2018; 61(9):3962-3983. DOI: 10.1021/acs.jmedchem.7b01903. View

13.

Lewis K . The Science of Antibiotic Discovery. Cell. 2020; 181(1):29-45. DOI: 10.1016/j.cell.2020.02.056. View

14.

Huigens 3rd R, Abouelhassan Y, Yang H . Phenazine Antibiotic-Inspired Discovery of Bacterial Biofilm-Eradicating Agents. Chembiochem. 2019; 20(23):2885-2902. PMC: 7325843. DOI: 10.1002/cbic.201900116. View

15.

Lewis K . Platforms for antibiotic discovery. Nat Rev Drug Discov. 2013; 12(5):371-87. DOI: 10.1038/nrd3975. View

16.

Lewis K . Persister cells. Annu Rev Microbiol. 2010; 64:357-72. DOI: 10.1146/annurev.micro.112408.134306. View

17.

Xiao T, Liu K, Huigens 3rd R . Progress towards a stable cephalosporin-halogenated phenazine conjugate for antibacterial prodrug applications. Bioorg Med Chem Lett. 2020; 30(22):127515. PMC: 7909726. DOI: 10.1016/j.bmcl.2020.127515. View

18.

Munita J, Arias C . Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016; 4(2). PMC: 4888801. DOI: 10.1128/microbiolspec.VMBF-0016-2015. View

19.

Yan J, Bassler B . Surviving as a Community: Antibiotic Tolerance and Persistence in Bacterial Biofilms. Cell Host Microbe. 2019; 26(1):15-21. PMC: 6629468. DOI: 10.1016/j.chom.2019.06.002. View

20.

Garrison A, Abouelhassan Y, Kallifidas D, Bai F, Ukhanova M, Mai V . Halogenated Phenazines that Potently Eradicate Biofilms, MRSA Persister Cells in Non-Biofilm Cultures, and Mycobacterium tuberculosis. Angew Chem Int Ed Engl. 2015; 54(49):14819-23. DOI: 10.1002/anie.201508155. View