Selective Chemical Inhibition of Quorum Sensing in Promotes Host Defense with Minimal Impact on Resistance

English version České info

New approaches are needed to lessen the burden of antibiotic resistant bacterial infections. One strategy is to develop therapies that target virulence which rely on host defense elements to clear the bacteria rather than direct antimicrobial killing. Quorum sensing is a bacterial signaling mechanism that often regulates virulence in medically relevant bacterial pathogens. Therefore, drugs that inhibit quorum sensing can promote host defense by rendering the pathogenic bacteria avirulent and/or less fit for survival within the host. Our work addressed this strategy in the pathogen Staphylococcus aureus which is the major cause of acute bacterial skin and soft tissue infections. We conducted a high throughput screen to identify compounds that could inhibit signaling by the quorum sensing operon, agr. We found a compound that we termed savirin (S. aureus virulence inhibitor) that could inhibit signaling by this operon. The drug helped the innate immune system in animals to clear bacteria that express this operon without affecting clearance of bacteria that do not have this operon. We addressed the mechanism of action of this compound and whether resistance or tolerance to this compound would likely develop. Our data indicate for the first time that host defense against S. aureus skin infections can be enhanced by chemical inhibition of agr-mediated quorum sensing.

Vyšlo v časopise: Selective Chemical Inhibition of Quorum Sensing in Promotes Host Defense with Minimal Impact on Resistance. PLoS Pathog 10(6): e32767. doi:10.1371/journal.ppat.1004174
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004174

Souhrn

Zdroje

1. SpellbergB, BartlettJG, GilbertDN (2013) The future of antibiotics and resistance. N Engl J Med 368: 299–302.

2. LaxminarayanR, DuseA, WattalC, ZaidiAK, WertheimHF, et al. (2013) Antibiotic resistance-the need for global solutions. Lancet Infect Dis 13: 1057–1098.

3. GrayB, HallP, GreshamH (2013) Targeting agr - and agr -like quorum sensing systems for development of common therapeutics to treat multiple gram-positive bacterial infections. Sensors (Basel) 13: 5130–5166.

4. RutherfordST, BasslerBL (2012) Bacterial quorum sensing: Its role in virulence and possibilities for its control. Cold Spring Harb Perspect Med 2 doi:10.1101/cshperspect.a012427

5. ZhuJ, KaufmannGF (2013) Quo vadis quorum quenching? Curr Opin Pharmacol 13: 688–698.

6. DefoirdtT, BrackmanG, CoenyeT (2013) Quorum sensing inhibitors: How strong is the evidence? Trends Microbiol 21: 619–624.

7. DefoirdtT, BoonN, BossierP (2010) Can bacteria evolve resistance to quorum sensing disruption? PLoS Pathog 6: e1000989.

8. GordonCP, WilliamsP, ChanWC (2013) Attenuating Staphylococcus aureus virulence gene regulation: A medicinal chemistry perspective. J Med Chem 56: 1389–1404.

9. TongSY, ChenLF, FowlerVGJr (2012) Colonization, pathogenicity, host susceptibility, and therapeutics for Staphylococcus aureus: What is the clinical relevance? Semin Immunopathol 34: 185–200.

10. DeLeoFR, ChambersHF (2009) Reemergence of antibiotic-resistant Staphylococcus aureus in the genomics era. J Clin Invest 119: 2464–2474.

11. ProctorRA (2012) Challenges for a universal Staphylococcus aureus vaccine. Clin Infect Dis 54: 1179–1186.

12. BelkaidY, NaikS (2013) Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol 14: 646–653.

13. LowyFD (1998) Staphylococcus aureus infections. N Engl J Med 339: 520–532.

14. LoughmanJA, FritzSA, StorchGA, HunstadDA (2009) Virulence gene expression in human community-acquired Staphylococcus aureus infection. J Infect Dis 199: 294–301 10.1086/595982.

15. CheungGY, WangR, KhanBA, SturdevantDE, OttoM (2011) Role of the accessory gene regulator agr in community-associated methicillin-resistant Staphylococcus aureus pathogenesis. Infect Immun 79: 1927–1935.

16. WrightJSIII, JinR, NovickRP (2005) Transient interference with staphylococcal quorum sensing blocks abscess formation. Proc Natl Acad Sci U S A 102: 1691–1696.

17. RothforkJM, TimminsGS, HarrisMN, ChenX, LusisAJ, et al. (2004) Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: New role for the NADPH oxidase in host defense. Proc Natl Acad Sci U S A 101: 13867–13872.

18. PetersonMM, MackJL, HallPR, AlsupAA, AlexanderSM, et al. (2008) Apolipoprotein B is an innate barrier against invasive Staphylococcus aureus infection. Cell Host Microbe 4: 555–566.

19. HallPR, ElmoreBO, SpangCH, AlexanderSM, Manifold-WheelerBC, et al. (2013) Nox2 modification of LDL is essential for optimal apolipoprotein B-mediated control of agr type III Staphylococcus aureus quorum-sensing. PLoS Pathog 9: e1003166.

20. ThoendelM, KavanaughJS, FlackCE, HorswillAR (2011) Peptide signaling in the staphylococci. Chem Rev 111: 117–151.

21. LipinskiCA, LombardoF, DominyBW, FeeneyPJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46: 3–26.

22. OttoM (2010) Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu Rev Microbiol 64: 143–162.

23. CogenAL, NizetV, GalloRL (2008) Skin microbiota: A source of disease or defence? Br J Dermatol 158: 442–455.

24. DenglerV, MeierPS, HeusserR, Berger-BachiB, McCallumN (2011) Induction kinetics of the Staphylococcus aureus cell wall stress stimulon in response to different cell wall active antibiotics. BMC Microbiol 11 16-2180-11-16.

25. AttiaAS, BensonMA, StauffDL, TorresVJ, SkaarEP (2010) Membrane damage elicits an immunomodulatory program in Staphylococcus aureus. PLoS Pathog 6: e1000802.

26. George CisarEA, GeisingerE, MuirTW, NovickRP (2009) Symmetric signalling within asymmetric dimers of the Staphylococcus aureus receptor histidine kinase AgrC. Mol Microbiol 74: 44–57.

27. LeonardPG, BezarIF, SidoteDJ, StockAM (2012) Identification of a hydrophobic cleft in the LytTR domain of AgrA as a locus for small molecule interactions that inhibit DNA binding. Biochemistry 51: 10035–10043.

28. GrosdidierA, ZoeteV, MichielinO (2011) SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res 39: W270–7.

29. SunF, LiangH, KongX, XieS, ChoH, et al. (2012) Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA. Proc Natl Acad Sci U S A 109: 9095–9100.

30. ShopsinB, EatonC, WassermanGA, MathemaB, AdhikariRP, et al. (2010) Mutations in agr do not persist in natural populations of methicillin-resistant Staphylococcus aureus. J Infect Dis 202: 1593–1599.

31. JensenRO, WinzerK, ClarkeSR, ChanWC, WilliamsP (2008) Differential recognition of Staphylococcus aureus quorum-sensing signals depends on both extracellular loops 1 and 2 of the transmembrane sensor AgrC. J Mol Biol 381: 300–309.

32. KhodaverdianV, PeshoM, TruittB, BollingerL, PatelP, et al. (2013) Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 57: 3645–3652.

33. MalachowaN, WhitneyAR, KobayashiSD, SturdevantDE, KennedyAD, et al. (2011) Global changes in Staphylococcus aureus gene expression in human blood. PLoS One 6: e18617.

34. ReissS, Pane-FarreJ, FuchsS, FrancoisP, LiebekeM, et al. (2012) Global analysis of the Staphylococcus aureus response to mupirocin. Antimicrob Agents Chemother 56: 787–804.

35. SongY, LundeCS, BentonBM, WilkinsonBJ (2012) Further insights into the mode of action of the lipoglycopeptide telavancin through global gene expression studies. Antimicrob Agents Chemother 56: 3157–3164.

36. CirzRT, JonesMB, GinglesNA, MinogueTD, JarrahiB, et al. (2007) Complete and SOS-mediated response of Staphylococcus aureus to the antibiotic ciprofloxacin. J Bacteriol 189: 531–539.

37. BensonMA, LiloS, WassermanGA, ThoendelM, SmithA, et al. (2011) Staphylococcus aureus regulates the expression and production of the staphylococcal superantigen-like secreted proteins in a rot-dependent manner. Mol Microbiol 81: 659–675.

38. VoyichJM, OttoM, MathemaB, BraughtonKR, WhitneyAR, et al. (2006) Is panton-valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease? J Infect Dis 194: 1761–1770.

39. ChoJS, ZussmanJ, DoneganNP, RamosRI, GarciaNC, et al. (2011) Noninvasive in vivo imaging to evaluate immune responses and antimicrobial therapy against Staphylococcus aureus and USA300 MRSA skin infections. J Invest Dermatol 131: 907–915.

40. KrishnaS, MillerLS (2012) Host-pathogen interactions between the skin and Staphylococcus aureus. Curr Opin Microbiol 15: 28–35.

41. GalloRL, HooperLV (2012) Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 12: 503–516.

42. SokolovskaA, BeckerCE, IpWK, RathinamVA, BrudnerM, et al. (2013) Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat Immunol 14: 543–553.

43. BoreE, LangsrudS, LangsrudO, RodeTM, HolckA (2007) Acid-shock responses in Staphylococcus aureus investigated by global gene expression analysis. Microbiology 153: 2289–2303.

44. StewardCD, RaneyPM, MorrellAK, WilliamsPP, McDougalLK, et al. (2005) Testing for induction of clindamycin resistance in erythromycin-resistant isolates of Staphylococcus aureus. J Clin Microbiol 43: 1716–1721.

45. SomervilleGA, BeresSB, FitzgeraldJR, DeLeoFR, ColeRL, et al. (2002) In vitro serial passage of Staphylococcus aureus: Changes in physiology, virulence factor production, and agr nucleotide sequence. J Bacteriol 184: 1430–1437.

46. GuoY, RamosRI, ChoJS, DoneganNP, CheungAL, et al. (2013) In vivo bioluminescence imaging to evaluate systemic and topical antibiotics against community-acquired methicillin-resistant Staphylococcus aureus-infected skin wounds in mice. Antimicrob Agents Chemother 57: 855–863.

47. SpellbergB, BoucherH, BradleyJ, DasA, TalbotG (2011) To treat or not to treat: Adjunctive antibiotics for uncomplicated abscesses. Ann Emerg Med 57: 183–185.

48. SmythDS, KaferJM, WassermanGA, VelickovicL, MathemaB, et al. (2012) Nasal carriage as a source of agr -defective Staphylococcus aureus bacteremia. J Infect Dis 206: 1168–1177.

49. EdwardsBS, YoungSM, Ivnitsky-SteeleI, YeRD, ProssnitzER, et al. (2009) High-content screening: Flow cytometry analysis. Methods Mol Biol 486: 151–165.

50. SidoteDJ, BarbieriCM, WuT, StockAM (2008) Structure of the Staphylococcus aureus AgrA LytTR domain bound to DNA reveals a beta fold with an unusual mode of binding. Structure 16: 727–735.

51. ForsythRA, HaselbeckRJ, OhlsenKL, YamamotoRT, XuH, et al. (2002) A genome-wide strategy for the identification of essential genes in Staphylococcus aureus. Mol Microbiol 43: 1387–1400.