Nonsteroidal antiinflammatory drugs alter antibiotic susceptibility and expression of virulence-related genes and protein A of Staphylococcus aureus

Nonsteroidal antiinflammatory drugs alter antibiotic susceptibility and expression of virulence-related genes and protein A of Staphylococcus aureus

Background/aim: Nonsteroidal antiinflammatory drugs (NSAIDs) including diclofenac, naproxen, ibuprofen, acetylsalicylic acid, and acetaminophen have been shown to have antimicrobial effects on various microorganisms. The aim of this study was to investigate the antibacterial effects of NSAIDs on Staphylococcus aureus. Materials and methods: Susceptibilities of S. aureus strains to NSAIDs with or without antimicrobials (moxifloxacin, vancomycin, ciprofloxacin, clindamycin, and gentamicin) were determined using the microdilution method and disk diffusion test. Expression levels of genes in the presence of drugs were investigated by real-time quantitative RT-PCR (qRT-PCR), and immunoblotting analysis was performed for staphylococcal protein A (SpA). Results: Our results showed that all NSAIDs were active against S. aureus strains with MIC values ranging from 195 µg/mL to 6250 µg/ mL. NSAIDs increased the antibiotic susceptibility of the strains, and diclofenac was found to be more effective than the other drugs. Drugs showed different effects on expression levels of virulence factor and/or regulatory genes. Immunoblotting analysis of SpA protein was mostly in accordance with qRT-PCR results. Conclusion: The regulatory/virulence factor genes and proteins of S. aureus investigated in this study may be reasonable targets for these drugs, and we suggest that the data may contribute to the field of infection control and antimicrobial resistance.Keywords: Gene expression, nonsteroidal antiinflammatory drugs, Staphylococcus aureus, antibiotic sensitivity, real-time qRT-PCR, immunoblotting

___

  • 1. Lowy F. Antimicrobial resistance: the example of Staphylococcus aureus. Journal of Clinical Investigation 2003; 111 (9): 1265- 1273. doi: 10.1172/JCI200318535
  • 2. Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clinical Microbiology Reviews 1997; 10 (4): 781-791. doi: 10.1128/CMR.10.4.781
  • 3. Seybold U, Kourbatova EV, Johnson JG, Halvosa SJ, Wang YF et al. Emergence of community-associated methicillinresistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clinical Infectious Diseases 2006; 42 (5): 647-656. doi:10.1016/ S0084-3873(08)70053-1
  • 4. Lentino JR, Narita M, Yu VL. New antimicrobial agents as therapy for resistant gram-positive cocci.European Journal of Clinical Microbiology & Infectious Diseases 2008; 27 (1): 3-15. doi: 10.1007/s10096-007-0389-y
  • 5. Brown DFJ, Edwards DI, Hawkey PM, Morrison D, Ridgway GL et al. Guidelines for the laboratory diagnosis and susceptibility testing of methicillin-resistant Staphylococcus aureus (MRSA). Journal of Antimicrobial Chemotherapy 2005; 56 (6): 1000- 1018. doi: 10.1093/jac/dki372
  • 6. Kaplan JB, Izano EA, Gopal P, Karwacki MT, Kim S et al. Low levels of beta-lactam antibiotics induce extracellular DNA release and biofilm formation in Staphylococcus aureus. MBio 2012; 3 (4): 1-8. doi: 10.1128/mBio.00198-12
  • 7. Zecconi A, Scali F. Staphylococcus aureus virulence factors in evasion from innate immune defenses in human and animal diseases. Immunology Letters 2013; 150 (1-2): 12-22. doi: 10.1016/j.imlet.2013.01.004
  • 8. Lowy F. Staphylococcus aureus infections. The New England Journal of Medicine 1998; 339 (27): 520-532. doi: 10.1056/ NEJM199808203390806
  • 9. Peacock SJ, Moore CE, Justice A, Kantzanou M, Story L et al. Virulent combinations of adhesin and toxin genes in natural populations of Staphylococcus aureus. Infection and Immunity 2002; 70 (9): 4987-4996. doi: 10.1128/IAI.70.9.4987
  • 10. Graille M, Stura EA, Corper AL, Sutton BJ, Taussig MJ et al. Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody : structural basis for recognition of B-cell receptors and superantigen activity. Proceedings of the National Academy of Sciences 2000; 97 (10): 5399-5404. doi: 10.1073/ pnas.97.10.5399
  • 11. Palmqvist N, Foster T, Tarkowski A, Josefsson E. Protein A is a virulence factor in Staphylococcus aureus arthritis and septic death. Microbial Pathogenesis 2002; 33 (5): 239-249. doi: 10.1006/mpat.2002.0533
  • 12. Baum C, Haslinger-Löffler B, Westh H, Boye K, Peters G et al. Non-spa-typeable clinical Staphylococcus aureus strains are naturally occurring protein A mutants. Journal of Clinical Microbiology 2009; 47 (11): 3624-3629. doi: 10.1128/ JCM.00941-09
  • 13. Kaatz GW, Demarco CE, Seo SM. MepR, a repressor of the Staphylococcus aureus MATE family multidrug efflux pump MepA, is a substrate-responsive regulatory protein. Antimicrobial Agents and Chemotherapy 2006; 50 (4): 1276- 1281. doi: 10.1128/AAC.50.4.1276
  • 14. Huang X, Aulabaugh A, Ding W, Kapoor B, Alksne L et al. Kinetic mechanism of Staphylococcus aureus sortase SrtA. Biochemistry 2003; 42 (38): 11307-11315. doi: 10.1021/bi034391g
  • 15. Frankel BA, Kruger RG, Robinson DE, Kelleher NL, McCafferty DG. Staphylococcus aureus sortase transpeptidase SrtA: insight into the kinetic mechanism and evidence for a reverse protonation catalytic mechanism, Biochemistry 2005; 44 (33): 11188-11200. doi: 10.1021/bi050141j
  • 16. Cheung AL, Eberhardt KJ, Chung E, Yeaman MR, Sullam PM et al. Dimished virulence of a sar-/agr- mutant of Staphylococcus aureus in the rabbit model of endocarditis, Journal of Clinical Investigation 1994; 94 (5): 1815-1822. doi: 10.1172/JCI117530
  • 17. Kristiansen JE. The antimicrobial activity of non-antibiotics. Report from a congress on the antimicrobial effect of drugs other than antibiotics on bacteria, viruses, protozoa, and other organisms. APMIS Suppl. 1992; 30: 7-14.
  • 18. De Lima Silva AA, Martins Silva P. Non-antibiotic compounds: the activity of the NSAID diclofenac on bacteriaa review. International Journal of Current Microbiology and Applied Sciences 2018; 7 (12): 340-351. doi: 10.20546/ ijcmas.2018.712.042
  • 19. CLSI. Performance standards for antimicrobial susceptibility testing; twenty third informational supplement. CLSI document M100-S23. Wayne, PA, USA: Clinical and Laboratory Standards Institute; 2013.
  • 20. Truong-Bolduc QC, Bolduc GR, Okumura R, Celino B, Bevis J et al. Implication of the NorB efflux pump in the adaptation of Staphylococcus aureus to growth at acid ph and in resistance to moxifloxacin. Antimicrobial Agents and Chemotherapy 2011; 55 (7): 3214-3219. doi: 10.1128/AAC.00289-11
  • 21. Bernardo K, Pakulat N, Fleer S, Schnaith A, Utermöhlen O et al. Subinhibitory concentrations of linezolid reduce Staphylococcus aureus virulence factor expression. Antimicrobial Agents and Chemotherapy 2004; 48 (2): 546-555. doi: 10.1128/AAC.48.2.546
  • 22. Otto MP, Martin E, Badiou C, Lebrun S, Bes M et al. Effects of subinhibitory concentrations of antibiotics on virulence factor expression by community-acquired methicillin-resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 2013; 68 (7): 1524-1532. doi: 10.1093/jac/dkt073
  • 23. Riordan RT, Muthaiyan A, Van Voorhies W, Price CT, Graham JE et al. Response of Staphylococcus aureus to salicylate challenge. Journal of Bacteriology 2007; 189 (1): 220-227. doi: 10.1128/ JB.01149-06
  • 24. Riordan JT, Dupre JM, Cantore-Matyi SA, Kumar-Singh A, Song Y et al. Alterations in the transcriptome and antibiotic susceptibility of Staphylococcus aureus grown in the presence of diclofenac. Annals of Clinical Microbiology and Antimicrobials 2011; 10 (30): 1-11. doi: 10.1186/1476-0711-10-30
  • 25. Dastidar SG, Ganguly K, Chaudhuri K, Chakrabarty AN. The anti-bacterial action of diclofenac shown by inhibition of DNA synthesis. International Journal of Antimicrobial Agents 2000; 14 (3): 249-251. doi: 10.1016/S0924-8579(99)00159-4
  • 26. Denkin S, Byrne S, Jie C, Zhang Y. Gene expression profiling analysis of Mycobacterium tuberculosisgenes in response to salicylate. Archives of Microbiology 2005; 184 (3): 152-157. doi: 10.1007/s00203-005-0037-9
  • 27. Muller E, Al-Attar J, Wolff AG, Farber BF. Mechanism of salicylate-mediated inhibition of biofilm in Staphylococcus epidermidis. The Journal of Infectious Diseases 1998; 177 (2): 501-503.
  • 28. Yin Z, Wang Y, Whittell LR, Jergic S, Liu M et al. DNA replication is the target for the antibacterial effects of nonsteroidal antiinflammatory drugs. Chemistry & Biology 2014; 21 (4): 481- 487. doi: 10.1016/j.chembiol.2014.02.009
  • 29. Obad J, Šušković J, Kos B. Antimicrobial activity of ibuprofen: New perspectives on an “old” non-antibiotic drug. European Journal of Pharmaceutical Sciences 2015; 71: 93-98. doi: 10.1016/j.ejps.2015.02.011
  • 30. Laudy AE, Mrowka A, Krajewska J, Tyski S, The influence of efflux pump inhibitors on the activity of non-antibiotic NSAIDS against gram-negative rods. PLoS One 2016; 11 (1): 1-16. doi: 10.1371/journal.pone.0147131
  • 31. Al-Janabi AAHS. In vitro antibacterial activity of ibuprofen and acetaminophen. Journal of Global Infectious Diseases 2020; 2 (2): 105-108. doi: 10.4103/0974-777X.62880
  • 32. Annadurai S, Guha-Thakurta A, Sa B, Ray SGDR, Chakrabarty AN. Experimental studies on synergism between aminoglycosides and the antimicrobial antiinflammatory agent diclofenac sodium. Journal of Chemotherapy 2002; 14 (1): 47- 53. doi: 10.1179/joc.2002.14.1.47
  • 33. Dutta NK, Annadurai S, Mazumdar K, Dastidar SG, Kristiansen JE et al. Potential management of resistant microbial infections with a novel non-antibiotic: the anti-inflammatory drug diclofenac sodium. International Journal of Antimicrobial Agents 2007; 30 (3): 242-249. doi: 10.1016/j.ijantimicag.2007.04.018
  • 34. Gustafson JE, Candelaria PV, Fisher SA, Goodridge JP, Lichocik TM et al. Growth in the presence of salicylate increases fluoroquinolone resistance in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 1999; 43 (4): 990-992.
  • 35. Price C, Lee I, Gustafson J. The effects of salicylate on bacteria. International Journal of Biochemistry & Cell Biology 2000; 32 (10): 1029-1043. doi: 10.1212/WNL.31.3.341
  • 36. Kupferwasser LI, Yeaman MR, Nast CC, Kupferwasser D, Xiong YQ et al. Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus. Journal of Clinical Investigation 2003; 112 (2): 222-233. doi: 10.1172/JCI200316876
  • 37. Manna AC, Cheung AL. Expression of SarX, a negative regulator of agr and exoprotein synthesis, is activated by MgrA in Staphylococcus aureus. Journal of Bacteriology 2006; 188 (12): 4288-4299. doi: 10.1128/JB.00297-06
  • 38. Ingavale S, Van Wamel W, Luong TT, Lee CY, Cheung AL. Rat/ MgrA, a regulator of autolysis, is a regulator of virulence genes in Staphylococcus aureus. Infection and Immunity 2005; 73 (3): 1423-1431. doi: 10.1128/IAI.73.3.1423-1431.2005
  • 39. Anderson KL, Roberts C, Disz T, Vonstein V, Hwang K et al. Characterization of the Staphylococcus aureus heat shock, cold shock, stringent, and SOS responses and their effects on logphase mRNA turnover. Journal of Bacteriology 2006; 188 (19): 6739-6756. doi: 10.1128/JB.00609-06
Turkish Journal of Medical Sciences-Cover
  • ISSN: 1300-0144
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK
Sayıdaki Diğer Makaleler

Which scoring system is better in association with exercise capacity and health status in noncystic fibrosis bronchiectasis patients?

Ali Kadri ÇIRAK, Yelda VAROL, Nimet AKSEL, Hülya Doğan ŞAHİN

Emergency department extracorporeal membrane oxygenation may also include noncardiac arrest patients

Mücahit AVCİL, Duygu EGE, Yunus Emre ÖZLÜER, Kezban ŞEKER YAŞAR

Vertebral compression fractures: Still an unpredictable aspect of osteoporosis

Fatma Yeşim KUTSAL, Gizem Olgu ERGİN ERGANİ

A practical method of drug provocation testing to prove tolerance to alternative drugs in drug hypersensitivity

Ebru DAMADOĞLU, Ali Fuat KALYONCU, Gül KARAKAYA, Özge ÖZTÜRK AKTAŞ

The effects of salt consumption habits on iodine status and thyroid functions during pregnancy

Mustafa ÖZBEK, Erman ÇAKAL, Bekir UÇAN, Mahmut APAYDIN, Özden ÖZDEMİR BAŞER, Taner DEMİRCİ

Frailty is associated with poor sleep quality in the oldest old

Muhammet Cemal KIZILARSLANOĞLU, Rana Tuna DOĞRUL, Olgun DENİZ, Süheyla ÇÖTELİ, Berna GÖKER, Çağatay ÇAVUŞOĞLU, Ali ÖNCÜL

Factors affecting mortality in geriatric patients hospitalized with COVID-19

Şermin BÖREKÇİ, Hakan YAVUZER, Alper DÖVENTAŞ, Günay CAN, Rabia BAĞ SOYTAŞ, Deniz SUNA ERDİNÇLER, Rıdvan KARAALİ, Veysel SUZAN, Mert Ahmet KUŞKUCU, Bora KORKMAZER, Damla ÜNAL, Pınar ARMAN, Tuğçe EMİROĞLU GEDİK

Risk factors predicting the development of diabetes mellitus and metabolic syndrome following gestational diabetes mellitus

Gülşah YENİDÜNYA YALIN, Bülent CAN, Sema ÇİFTÇİ, Nevin DİNÇÇAĞ

Effects of sitagliptin on ß-adrenoceptor mediated relaxation in streptozotocin-diabetic rat aorta

Ayhanım Elif MÜDERRİSOĞLU, Betül Rabia ERDOĞAN, Zeynep Elif YEŞİLYURT, Ceren UYAR BOZTAŞ, İrem KARAÖMERLİOĞLU, Vecdi Melih ALTAN, Ebru ARIOĞLU İNAN

Fatigue and its relationship with disease-related factors in patients with systemic sclerosis: A cross-sectional study

Ahmet Merih BİRLİK, Sevgi ÖZALEVLİ, Hazal YAKUT