Novel Riboswitch Ligand Analogs as Selective Inhibitors of Guanine-Related Metabolic Pathways

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Riboswitches are regulatory elements modulating gene expression in response to specific metabolite binding. It has been recently reported that riboswitch agonists may exhibit antimicrobial properties by binding to the riboswitch domain. Guanine riboswitches are involved in the regulation of transport and biosynthesis of purine metabolites, which are critical for the nucleotides cellular pool. Upon guanine binding, these riboswitches stabilize a 5′-untranslated mRNA structure that causes transcription attenuation of the downstream open reading frame. In principle, any agonistic compound targeting a guanine riboswitch could cause gene repression even when the cell is starved for guanine. Antibiotics binding to riboswitches provide novel antimicrobial compounds that can be rationally designed from riboswitch crystal structures. Using this, we have identified a pyrimidine compound (PC1) binding guanine riboswitches that shows bactericidal activity against a subgroup of bacterial species including well-known nosocomial pathogens. This selective bacterial killing is only achieved when guaA, a gene coding for a GMP synthetase, is under the control of the riboswitch. Among the bacterial strains tested, several clinical strains exhibiting multiple drug resistance were inhibited suggesting that PC1 targets a different metabolic pathway. As a proof of principle, we have used a mouse model to show a direct correlation between the administration of PC1 and the reduction of Staphylococcus aureus infection in mammary glands. This work establishes the possibility of using existing structural knowledge to design novel guanine riboswitch-targeting antibiotics as powerful and selective antimicrobial compounds. Particularly, the finding of this new guanine riboswitch target is crucial as community-acquired bacterial infections have recently started to emerge.

Vyšlo v časopise: Novel Riboswitch Ligand Analogs as Selective Inhibitors of Guanine-Related Metabolic Pathways. PLoS Pathog 6(4): e32767. doi:10.1371/journal.ppat.1000865
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000865

Souhrn

Zdroje

1. BlountKF

BreakerRR

2006 Riboswitches as antibacterial drug targets. Nat Biotechnol 24 1558 1564

2. TalbotGH

BradleyJ

EdwardsJEJr

GilbertD

ScheldM

2006 Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 42 657 668

3. PopovichKJ

HotaB

WeinsteinRA

2008 Treatment of community-associated methicillin-resistant staphylococcus aureus. Curr Infect Dis Rep 10 411 420

4. ValentiniP

ParisiG

MonacoM

CreaF

SpanuT

2008 An uncommon presentation for a severe invasive infection due to methicillin-resistant Staphylococcus aureus clone USA300 in Italy: a case report. Ann Clin Microbiol Antimicrob 7 11

5. PofelskiJ

PaveseP

BrionJP

MarrakchiC

GayE

2003 Staphylococcus aureus meningitis with intermediate sensitivity to glycopeptides. Therapeutic indications. Presse Med 32 217 220

6. LooVG

PoirierL

MillerMA

OughtonM

LibmanMD

2005 A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 353 2442 2449

7. KuijperEJ

CoignardB

TullP

2006 Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect 12 Suppl 6 2 18

8. KnowlesDJ

FoloppeN

MatassovaNB

MurchieAI

2002 The bacterial ribosome, a promising focus for structure-based drug design. Curr Opin Pharmacol 2 501 506

9. MonaghanRL

BarrettJF

2006 Antibacterial drug discovery–then, now and the genomics future. Biochem Pharmacol 71 901 909

10. SteitzTA

2005 On the structural basis of peptide-bond formation and antibiotic resistance from atomic structures of the large ribosomal subunit. FEBS Lett 579 955 958

11. BlountKF

WangJX

LimJ

SudarsanN

BreakerRR

2007 Antibacterial lysine analogs that target lysine riboswitches. Nat Chem Biol 3 44 49

12. SudarsanN

Cohen-ChalamishS

NakamuraS

EmilssonGM

BreakerRR

2005 Thiamine pyrophosphate riboswitches are targets for the antimicrobial compound pyrithiamine. Chem Biol 12 1325 1335

13. LeeER

BlountKF

BreakerRR

2009 Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression. RNA Biol 6

14. OttE

StolzJ

LehmannM

MackM

2009 The RFN riboswitch of Bacillus subtilis is a target for the antibiotic roseoflavin produced by Streptomyces davawensis. RNA Biol 6 276 280

15. KimJN

BlountKF

LimJ

LinkKH

BreakerR

2009 Design and antimicrobial action of purine analogs that bind guanine riboswitches. ACS Chem Biol 4 915 927

16. AtaideSF

WilsonSN

DangS

RogersTE

RoyB

2007 Mechanisms of resistance to an amino acid antibiotic that targets translation. ACS Chem Biol 2 819 827

17. WittorfJH

GublerCJ

1971 Coenzyme binding in yeast pyruvate decarboxylase. Kinetic studies with thiamine diphosphate analogues. Eur J Biochem 22 544 550

18. HeinrichPC

SteffenH

JanserP

WissO

1972 Studies on the reconstitution of apotransketolase with thiamine pyrophosphate and analogs of the coenzyme. Eur J Biochem 30 533 541

19. WoolleyDW

1951 An enzymatic study of the mode of action of pyrithiamine (neopyrithiamine). J Biol Chem 191 43 54

20. KozminSG

SchaaperRM

ShcherbakovaPV

KulikovVN

NoskovVN

1998 Multiple antimutagenesis mechanisms affect mutagenic activity and specificity of the base analog 6-N-hydroxylaminopurine in bacteria and yeast. Mutat Res 402 41 50

21. GilbertSD

MediatoreSJ

BateyRT

2006 Modified pyrimidines specifically bind the purine riboswitch. J Am Chem Soc 128 14214 14215

22. ShimaokaM

TakenakaY

MiharaY

KurahashiO

KawasakiH

2006 Effects of xapA and guaA disruption on inosine accumulation in Escherichia coli. Biosci Biotechnol Biochem 70 3069 3072

23. KobayashiK

EhrlichSD

AlbertiniA

AmatiG

AndersenKK

2003 Essential Bacillus subtilis genes. Proc Natl Acad Sci U S A 100 4678 4683

24. KimJN

BreakerRR

2008 Purine sensing by riboswitches. Biol Cell 100 1 11

25. MandalM

BoeseB

BarrickJE

WinklerWC

BreakerRR

2003 Riboswitches control fundamental biochemical pathways in Bacillus subtilis and other bacteria. Cell 113 577 586

26. SerganovA

YuanYR

PikovskayaO

PolonskaiaA

MalininaL

2004 Structural basis for discriminative regulation of gene expression by adenine- and guanine-sensing mRNAs. Chem Biol 11 1729 1741

27. BateyRT

GilbertSD

MontangeRK

2004 Structure of a natural guanine-responsive riboswitch complexed with the metabolite hypoxanthine. Nature 432 411 415

28. MulhbacherJ

LafontaineDA

2007 Ligand recognition determinants of guanine riboswitches Nucleic Acids Res 35 5568 5580

29. PorwalS

LalS

CheemaS

KaliaVC

2009 Phylogeny in aid of the present and novel microbial lineages: diversity in Bacillus. PLoS ONE 4 e4438 doi:10.1371/journal.pone.0004438

30. MoisanH

BrouilletteE

JacobCL

Langlois-BeginP

MichaudS

2006 Transcription of virulence factors in Staphylococcus aureus small-colony variants isolated from cystic fibrosis patients is influenced by SigB. J Bacteriol 188 64 76

31. BischoffM

DunmanP

KormanecJ

MacapagalD

MurphyE

2004 Microarray-based analysis of the Staphylococcus aureus sigmaB regulon. J Bacteriol 186 4085 4099

32. SearsPM

McCarthyKK

2003 Management and treatment of staphylococcal mastitis. Vet Clin North Am Food Anim Pract 19 171 185

33. BrouilletteE

MalouinF

2005 The pathogenesis and control of Staphylococcus aureus-induced mastitis: study models in the mouse. Microbes Infect 7 560 568

34. MayerSJ

WatermanAE

KeenPM

CravenN

BourneFJ

1988 Oxygen concentration in milk of healthy and mastitic cows and implications of low oxygen tension for the killing of Staphylococcus aureus by bovine neutrophils. J Dairy Res 55 513 519

35. JiY

ZhangB

VanSF

Horn

WarrenP

2001 Identification of critical staphylococcal genes using conditional phenotypes generated by antisense RNA. Science 293 2266 2269

36. WilsonTL

JeffersJ

Rapp-GabrielsonVJ

MartinS

KleinLK

2007 A novel signature-tagged mutagenesis system for Streptococcus suis serotype 2. Vet Microbiol 122 135 145

37. McFarlandWC

StockerBA

1987 Effect of different purine auxotrophic mutations on mouse-virulence of a Vi-positive strain of Salmonella dublin and of two strains of Salmonella typhimurium. Microb Pathog 3 129 141

38. RussoTA

JodushST

BrownJJ

JohnsonJR

1996 Identification of two previously unrecognized genes (guaA and argC) important for uropathogenesis. Mol Microbiol 22 217 229

39. SamantS

LeeH

GhassemiM

ChenJ

CookJL

2008 Nucleotide biosynthesis is critical for growth of bacteria in human blood. PLoS Pathog 4 e37 doi:10.1371/journal.ppat.0040037

40. SwannPF

WatersTR

MoultonDC

XuYZ

ZhengQ

1996 Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273 1109 1111

41. LemayJF

PenedoJC

TremblayR

LilleyDM

LafontaineDA

2006 Folding of the adenine riboswitch. Chem Biol 13 857 868

42. BrouilletteE

GrondinG

TalbotBG

MalouinF

2005 Inflammatory cell infiltration as an indicator of Staphylococcus aureus infection and therapeutic efficacy in experimental mouse mastitis. Vet Immunol Immunopathol 104 163 169

43. MazzariolA

CornagliaG

NikaidoH

2000 Contributions of the AmpC beta-lactamase and the AcrAB multidrug efflux system in intrinsic resistance of Escherichia coli K-12 to beta-lactams. Antimicrob Agents Chemother 44 1387 1390

44. SampsonBA

MisraR

BensonSA

1989 Identification and characterization of a new gene of Escherichia coli K-12 involved in outer membrane permeability. Genetics 122 491 501

45. TaylorEC

LouxHM

FalcoEA

HitchingsGH

1955 Pyrimidopteridines by oxidative self-condensation of aminopyrimidines. J Am Chem Soc 77 2243 2248

46. JonesME

BoeninkNM

VerhoefJ

KohrerK

SchmitzFJ

2000 Multiple mutations conferring ciprofloxacin resistance in Staphylococcus aureus demonstrate long-term stability in an antibiotic-free environment. J Antimicrob Chemother 45 353 356

47. WichelhausT

SchaferV

BradeV

BoddinghausB

2001 Differential effect of rpoB mutations on antibacterial activities of rifampicin and KRM-1648 against Staphylococcus aureus. J Antimicrob Chemother 47 153 156