A Rhein-Based Derivative Targets

Overview

Journal Antibiotics (Basel)

Specialty Pharmacology

Date 2024 Sep 28

PMID 39335055

Authors

Xiaojia Liu

Yuan Liu

Meirong Song

Kui Zhu

Jianzhong Shen

Affiliations

Soon will be listed here.

Abstract

The rise in antibiotic-resistant bacteria highlights the need for novel antimicrobial agents. This study presents the design and synthesis of a series of rhein (RH)-derived compounds with improved antimicrobial properties. The lead compound, RH, exhibited a potent antibacterial activity against () isolates, with minimum inhibitory concentrations (MICs) ranging from 8 to 16 μg/mL. RH disrupted bacterial membrane stability, hindered metabolic processes, and led to an increase in reactive oxygen species (ROS) production. These mechanisms were confirmed through bacterial growth inhibition assays, membrane function assessments, and ROS detection. Notably, RH outperformed the parent compound RH and demonstrated bactericidal effects in . The findings suggest that RH is a promising candidate for further development as an antimicrobial agent against Gram-positive pathogens, addressing the urgent need for new therapies.

References

Carmeli Y . Strategies for managing today's infections. Clin Microbiol Infect. 2008; 14 Suppl 3:22-31. DOI: 10.1111/j.1469-0691.2008.01957.x. View

Farha M, Verschoor C, Bowdish D, Brown E . Collapsing the proton motive force to identify synergistic combinations against Staphylococcus aureus. Chem Biol. 2013; 20(9):1168-78. DOI: 10.1016/j.chembiol.2013.07.006. View

Deng T, Du J, Yin Y, Cao B, Wang Z, Zhang Z . Rhein for treating diabetes mellitus: A pharmacological and mechanistic overview. Front Pharmacol. 2023; 13:1106260. PMC: 9868719. DOI: 10.3389/fphar.2022.1106260. View

Bakker E, Mangerich W . Interconversion of components of the bacterial proton motive force by electrogenic potassium transport. J Bacteriol. 1981; 147(3):820-6. PMC: 216117. DOI: 10.1128/jb.147.3.820-826.1981. View

Theuretzbacher U, Bush K, Harbarth S, Paul M, Rex J, Tacconelli E . Critical analysis of antibacterial agents in clinical development. Nat Rev Microbiol. 2020; 18(5):286-298. DOI: 10.1038/s41579-020-0340-0. View

Bakkeren E, Diard M, Hardt W . Evolutionary causes and consequences of bacterial antibiotic persistence. Nat Rev Microbiol. 2020; 18(9):479-490. DOI: 10.1038/s41579-020-0378-z. View

Fernand V, Losso J, Truax R, Villar E, K Bwambok D, O Fakayode S . Rhein inhibits angiogenesis and the viability of hormone-dependent and -independent cancer cells under normoxic or hypoxic conditions in vitro. Chem Biol Interact. 2011; 192(3):220-32. DOI: 10.1016/j.cbi.2011.03.013. View

Pei R, Jiang Y, Lei G, Chen J, Liu M, Liu S . Rhein Derivatives, A Promising Pivot?. Mini Rev Med Chem. 2020; 21(5):554-575. DOI: 10.2174/1389557520666201109120855. View

Conlon B, Rowe S, Brown Gandt A, Nuxoll A, Donegan N, Zalis E . Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat Microbiol. 2016; 1:16051. DOI: 10.1038/nmicrobiol.2016.51. View

10.

Beganovic M, Luther M, Rice L, Arias C, Rybak M, LaPlante K . A Review of Combination Antimicrobial Therapy for Enterococcus faecalis Bloodstream Infections and Infective Endocarditis. Clin Infect Dis. 2018; 67(2):303-309. PMC: 6248357. DOI: 10.1093/cid/ciy064. View

11.

Logviniuk D, Fridman M . Serum Prevents Interactions between Antimicrobial Amphiphilic Aminoglycosides and Plasma Membranes. ACS Infect Dis. 2020; 6(12):3212-3223. DOI: 10.1021/acsinfecdis.0c00588. View

12.

Fillingame R . Coupling H+ transport and ATP synthesis in F1F0-ATP synthases: glimpses of interacting parts in a dynamic molecular machine. J Exp Biol. 1997; 200(Pt 2):217-24. DOI: 10.1242/jeb.200.2.217. View

13.

Cheng L, Chen Q, Pi R, Chen J . A research update on the therapeutic potential of rhein and its derivatives. Eur J Pharmacol. 2021; 899:173908. DOI: 10.1016/j.ejphar.2021.173908. View

14.

Chen C, Liang C, Wang T, Shen J, Ling F, Jiang H . Antiviral, antioxidant, and anti-inflammatory activities of rhein against white spot syndrome virus infection in red swamp crayfish (). Microbiol Spectr. 2023; 11(6):e0104723. PMC: 10714825. DOI: 10.1128/spectrum.01047-23. View

15.

Mehershahi K, Chen S . DNA methylation by three Type I restriction modification systems of Escherichia coli does not influence gene regulation of the host bacterium. Nucleic Acids Res. 2021; 49(13):7375-7388. PMC: 8287963. DOI: 10.1093/nar/gkab530. View

16.

Folliero V, DellAnnunziata F, Roscetto E, Amato A, Gasparro R, Zannella C . Rhein: A novel antibacterial compound against Streptococcus mutans infection. Microbiol Res. 2022; 261:127062. DOI: 10.1016/j.micres.2022.127062. View

17.

Zhang K, Du Y, Si Z, Liu Y, Turvey M, Raju C . Enantiomeric glycosylated cationic block co-beta-peptides eradicate Staphylococcus aureus biofilms and antibiotic-tolerant persisters. Nat Commun. 2019; 10(1):4792. PMC: 6803644. DOI: 10.1038/s41467-019-12702-8. View

18.

Nitulescu G, Nicorescu I, Olaru O, Ungurianu A, Mihai D, Zanfirescu A . Molecular Docking and Screening Studies of New Natural Sortase A Inhibitors. Int J Mol Sci. 2017; 18(10). PMC: 5666896. DOI: 10.3390/ijms18102217. View

19.

Howden B, Giulieri S, Wong Fok Lung T, Baines S, Sharkey L, Lee J . Staphylococcus aureus host interactions and adaptation. Nat Rev Microbiol. 2023; 21(6):380-395. PMC: 9882747. DOI: 10.1038/s41579-023-00852-y. View

20.

Kalelkar P, Riddick M, Garcia A . Biomaterial-based delivery of antimicrobial therapies for the treatment of bacterial infections. Nat Rev Mater. 2022; 7(1):39-54. PMC: 8938918. DOI: 10.1038/s41578-021-00362-4. View