Identification of a Potent Small-molecule Inhibitor of Bacterial DNA Repair That Potentiates Quinolone Antibiotic Activity in Methicillin-resistant Staphylococcus Aureus

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2019 Jul 17

PMID 31307763

Citations 11

Authors

Carine S Q Lim

Kam Pou Ha

Rebecca S Clarke

Leigh-Anne Gavin

Declan T Cook

Jennie A Hutton

Charlotte L Sutherell

Andrew M Edwards

Lindsay E Evans

Edward W Tate

Thomas Lanyon-Hogg

Affiliations

Soon will be listed here.

Abstract

The global emergence of antibiotic resistance is one of the most serious challenges facing modern medicine. There is an urgent need for validation of new drug targets and the development of small molecules with novel mechanisms of action. We therefore sought to inhibit bacterial DNA repair mediated by the AddAB/RecBCD protein complexes as a means to sensitize bacteria to DNA damage caused by the host immune system or quinolone antibiotics. A rational, hypothesis-driven compound optimization identified IMP-1700 as a cell-active, nanomolar potency compound. IMP-1700 sensitized multidrug-resistant Staphylococcus aureus to the fluoroquinolone antibiotic ciprofloxacin, where resistance results from a point mutation in the fluoroquinolone target, DNA gyrase. Cellular reporter assays indicated IMP-1700 inhibited the bacterial SOS-response to DNA damage, and compound-functionalized Sepharose successfully pulled-down the AddAB repair complex. This work provides validation of bacterial DNA repair as a novel therapeutic target and delivers IMP-1700 as a tool molecule and starting point for therapeutic development to address the pressing challenge of antibiotic resistance.

Citing Articles

Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance.

Bradbury J, Hodgkinson T, Thomas A, Tanwar O, La Monica G, Rogga V Chem Sci. 2024; 15(25):9620-9629.

PMID: 38939155 PMC: 11206376. DOI: 10.1039/d4sc00995a.

Prokaryotic DNA Crossroads: Holliday Junction Formation and Resolution.

Nautiyal A, Thakur M ACS Omega. 2024; 9(11):12515-12538.

PMID: 38524412 PMC: 10956419. DOI: 10.1021/acsomega.3c09866.

Mechanistic insight into the repair of C8-linked pyrrolobenzodiazepine monomer-mediated DNA damage.

Joseph A, Nahar K, Daw S, Hasan M, Lo R, Le T RSC Med Chem. 2022; 13(12):1621-1633.

PMID: 36561066 PMC: 9749960. DOI: 10.1039/d2md00194b.

Structures of RecBCD in complex with phage-encoded inhibitor proteins reveal distinctive strategies for evasion of a bacterial immunity hub.

Wilkinson M, Wilkinson O, Feyerherm C, Fletcher E, Wigley D, Dillingham M Elife. 2022; 11.

PMID: 36533901 PMC: 9836394. DOI: 10.7554/eLife.83409.

Iron Chelator DIBI Suppresses Formation of Ciprofloxacin-Induced Antibiotic Resistance in .

Allan D, Holbein B Antibiotics (Basel). 2022; 11(11).

PMID: 36421286 PMC: 9687013. DOI: 10.3390/antibiotics11111642.

References

Henderson M, Kreuzer K . Functions that Protect Escherichia coli from Tightly Bound DNA-Protein Complexes Created by Mutant EcoRII Methyltransferase. PLoS One. 2015; 10(5):e0128092. PMC: 4437897. DOI: 10.1371/journal.pone.0128092. View

Amundsen S, Spicer T, Karabulut A, Londono L, Eberhart C, Fernandez Vega V . Small-molecule inhibitors of bacterial AddAB and RecBCD helicase-nuclease DNA repair enzymes. ACS Chem Biol. 2012; 7(5):879-91. PMC: 3356449. DOI: 10.1021/cb300018x. View

Lopez E, Elez M, Matic I, Blazquez J . Antibiotic-mediated recombination: ciprofloxacin stimulates SOS-independent recombination of divergent sequences in Escherichia coli. Mol Microbiol. 2007; 64(1):83-93. DOI: 10.1111/j.1365-2958.2007.05642.x. View

Blaser M . Antibiotic overuse: Stop the killing of beneficial bacteria. Nature. 2011; 476(7361):393-4. DOI: 10.1038/476393a. View

Andersson M, MacGowan A . Development of the quinolones. J Antimicrob Chemother. 2003; 51 Suppl 1:1-11. DOI: 10.1093/jac/dkg212. View

Blower T, Williamson B, Kerns R, Berger J . Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2016; 113(7):1706-13. PMC: 4763791. DOI: 10.1073/pnas.1525047113. View

Tamae C, Liu A, Kim K, Sitz D, Hong J, Becket E . Determination of antibiotic hypersensitivity among 4,000 single-gene-knockout mutants of Escherichia coli. J Bacteriol. 2008; 190(17):5981-8. PMC: 2519525. DOI: 10.1128/JB.01982-07. View

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

Horsburgh M, Aish J, White I, Shaw L, Lithgow J, Foster S . sigmaB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325-4. J Bacteriol. 2002; 184(19):5457-67. PMC: 135357. DOI: 10.1128/JB.184.19.5457-5467.2002. View

10.

TOPLISS J . A manual method for applying the Hansch approach to drug design. J Med Chem. 1977; 20(4):463-9. DOI: 10.1021/jm00214a001. View

11.

Payne D, Gwynn M, Holmes D, Pompliano D . Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2006; 6(1):29-40. DOI: 10.1038/nrd2201. View

12.

Anderson D, Kowalczykowski S . The translocating RecBCD enzyme stimulates recombination by directing RecA protein onto ssDNA in a chi-regulated manner. Cell. 1997; 90(1):77-86. DOI: 10.1016/s0092-8674(00)80315-3. View

13.

Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M . Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol. 2006; 2:2006.0008. PMC: 1681482. DOI: 10.1038/msb4100050. View

14.

Ju K, Parales R . Nitroaromatic compounds, from synthesis to biodegradation. Microbiol Mol Biol Rev. 2010; 74(2):250-72. PMC: 2884413. DOI: 10.1128/MMBR.00006-10. View

15.

Sun D, Hurley L . Structure-activity relationships of (+)-CC-1065 analogues in the inhibition of helicase-catalyzed unwinding of duplex DNA. J Med Chem. 1992; 35(10):1773-82. DOI: 10.1021/jm00088a012. View

16.

Domagala J, Hanna L, Heifetz C, Hutt M, Mich T, Sanchez J . New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay. J Med Chem. 1986; 29(3):394-404. DOI: 10.1021/jm00153a015. View

17.

Wilkinson M, Troman L, Wan Nur Ismah W, Chaban Y, Avison M, Dillingham M . Structural basis for the inhibition of RecBCD by Gam and its synergistic antibacterial effect with quinolones. Elife. 2016; 5. PMC: 5218532. DOI: 10.7554/eLife.22963. View

18.

Laponogov I, Sohi M, Veselkov D, Pan X, Sawhney R, Thompson A . Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases. Nat Struct Mol Biol. 2009; 16(6):667-9. DOI: 10.1038/nsmb.1604. View

19.

Karu A, Linn S . Uncoupling of the recBC ATPase from DNase by DNA crosslinked with psoralen. Proc Natl Acad Sci U S A. 1972; 69(10):2855-9. PMC: 389661. DOI: 10.1073/pnas.69.10.2855. View

20.

Cirz R, Chin J, Andes D, de Crecy-Lagard V, Craig W, Romesberg F . Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol. 2005; 3(6):e176. PMC: 1088971. DOI: 10.1371/journal.pbio.0030176. View