INVESTIGATION OF ANTIMICROBIAL AND ANTI-QUORUM SENSING PROPERTIES OF SOME DERIVATIVES OF CEPHALOSPORANIC ACID, CIPROFLOXACIN, NORFLOXACIN, AND PENICILLANIC ACID

Abstract

Objective: The rapid increase of antibiotic resistance among bacteria is a serious public health problem. Studies have focused on the discovery of new antibiotic molecules and the development of new therapeutic strategies to combat these resistant bacteria. Once it was known that pathogenic bacteria regulate synthesis of virulence factors by the quorum sensing (QS) mechanism, QS inhibition became an attractive target for antibacterial treatment. This study aimed to investigate the antimicrobial activities and anti-QS properties of 16 derivatives of cephalosporanic acid, ciprofloxacin, norfloxacin, and penicillanic acid.

Methods: Antimicrobial activity of the derivatives was tested by the agar well diffusion method against various microorganisms. The minimum inhibitory concentration (MIC) of effective derivatives was assessed by the broth microdilution method. Anti-QS properties were investigated using the soft agar method, observing inhibition of violacein production in Chromobacterium violaceum. The data were compared statistically.

Results: Six norfloxacin derivatives displayed antimicrobial activity against a number of organisms, three of which were more effective than control antibiotics (p<0.05) against some organisms. One ciprofloxacin derivative demonstrated antimicrobial activity against all tested bacteria and was more effective against some bacteria than control antibiotic (p<0.05).  The MIC values of these six norfloxacin and one ciprofloxacin derivatives were between 0.04–6.25 µg/mL and 0.04–3.12 µg/mL, respectively. A cephalosporanic acid and a penicillanic acid derivative displayed anti-QS properties.

Conclusion: This study shows that some new derivatives of cephalosporanic acid, ciprofloxacin, norfloxacin, and penicillanic acid may have potential for development of new antibacterial and anti-QS agents.

Keywords

• Chromobacterium violaceum
• antibiotic resistance
• derivatives
• antimicrobial tests

BAZI SEFALOSPORANİK ASİT, SİPROFLOKSASİN, NORFLOKSASİN VE PENİCİLLANİK ASİT TÜREVLERİNİN ANTİMİKROBİYAL VE ANTI-QUORUM SENSING ÖZELLİKLERİNİN ARAŞTIRILMASI

Abstract

Amaç: Bakteriler arasında antibiyotik direncinin hızla artışı halk sağlığı açısından ciddi bir problem oluşturmaktadır. Çalışmalar, yeni antimikrobiyal moleküllerin keşfi ve dirençli bakterilerle mücadelede yeni tedavi stratejilerinin geliştirilmesi üzerine yoğunlaşmıştır. Patojenik bakterilerin, quorum sensing (QS) mekanizmasını kullanarak virülans faktörlerinin sentezini düzenlediği bulunduktan sonra, QS inhibisyonu antibakteriyel tedavi için cazip bir hedef haline gelmiştir. Bu çalışmada sefalosporanik asit, siprofloksasin, norfloksasin ve penisillanik asit türevi 16 maddenin antimikrobiyal aktivitelerinin ve anti-QS özelliklerinin araştırılması amaçlandı.

Yöntem: Maddelerin antimikrobiyal aktiviteleri çeşitli mikroorganizmalara karşı agar kuyucuk diffüzyon yöntemi ile test edildi. Etki gösteren maddelerin minimum inhibisyon konsantrasyon (MİK) değerleri sıvı mikrodilüsyon yöntemi ile belirlendi. Maddelerin anti-QS özellikleri Chromobacterium violaceum raportör suşunda viyolasin inhibisyonu üzerine yarı-katı agar yöntemi ile araştırıldı. Veriler istatistiksel olarak karşılaştırıldı.

Bulgular: Altı norfloksasin türevi test edilen bakterilerin bir kısmına karşı antimikrobiyal aktivite göstermiş olup üç türevin bazı organizmalara karşı kontrol antibiyotiklerden daha etkili olduğu tespit edildi (p<0,05). Bir siprofloksasin türevi, test edilen tüm bakterilere karşı antimikrobiyal aktiviteye sahip olup bakterilerin bir kısmına karşı kontrol antibiyotiğinden daha etkili olduğu belirlendi (p<0,05). Altı norfloksasin ve bir siprofloksasin türevinin MİK değerleri, sırasıyla 0,04–6,25 µg/mL ve 0,04–3,12 µg/mL aralığında tespit edildi. Bir sefalosporanik asit ve bir penisillanik asit türevinin anti-QS özellik gösterdiği belirlendi.

Sonuç: Bu sonuçlar, bazı yeni sefalosporanik asit, siprofloksasin, norfloksasin ve penicillanik asit türevlerinin yeni antibakteriyel ve anti-QS ajanların geliştirilmesinde potansiyel moleküller olabileceğini göstermiştir.

Keywords

• Chromobacterium violaceum
• antibiyotik direnci
• türevler
• antimikrobiyal testler

References

1. World Health Organization (2018, February 15). Antimicrobial resistance. Available from: https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance (accessed on 11 November 2019).
2. Alanis AJ. Resistance to antibiotics: are we in the post-antibiotic era? Arch Med Res. 2005;36:697–705. doi: 10.1016/j.arcmed.2005.06.009
3. El-Sharer S, Shaaban M, Barwa R, Hassan R. Control of quorum sensing and virulence factors of Pseudomonas aeruginosa using phenylalanine arginyl β-naphthylamide. J Med Microbiol. 2016;65:1194–1204. doi: 10.1099/jmm.0.000327
4. Papenfort K, Bassler BL. Quorum sensing signal-response systems in gram-negative bacteria. Nat Rev Microbiol. 2016;14:576–588. doi: 10.1038/nrmicro.2016.89
5. Eberl L, Winson MK, Sternberg C, et al. Involvement of N-acyl-L-hormoserine lactone autoinducers in controlling the multicellular behaviour of Serratia liquefaciens. Mol Microbiol. 1996;20:127–136. doi: 10.1111/j.1365-2958.1996.tb02495.x
6. McClean KH, Winson MK, Fish L, et al. Quorum sensing and Chromobacterium violaceum: exploitation of violacein production and inhibition for the detection of N-acylhomoserine lactones. Microbiol. 1997;143:3703–3711. doi: 10.1099/00221287-143-12-3703
7. Rice SA, Koh KS, Queck SY, Labbate M, Lam KW, Kjelleberg S. Biofilm formation and sloughing in Serratia marcescens are controlled by quorum sensing and nutrient cues. J Bacteriol. 2005;187:3477–3485. doi: 10.1128/JB.187.10.3477-3485.2005
8. Tinaz-Bosgelmez G, Ulusoy S, Ugur A, Ceylan O. Inhibition of quorum sensing-regulated behaviors by Scorzonera sandrasica. Curr Microbiol. 2007;55:114–118. doi: 10.1007/s00284-006-0624-2

9. Kalia VC. Quorum sensing inhibitors: an overview. Biotechnol Adv. 2013; 31:224–245. doi: 10.1016/j.biotechadv.2012.10.004
10. Morohoshi T, Kato M, Fukamachi K, Kato N, Ikeda T. N-acylhomoserine lactone regulates violacein production in Chromobacterium violaceum type strain ATCC 12472. FEMS Microbiol Lett. 2008;279:124–130. doi: 10.1111/j.1574-6968.2007.01016.x
11. McLean RJC, Pierson LS, Fuqua CA. Simple screening protocol for the identification of quorum signal antagonists. J Microbiol Methods. 2004;58:351–360. doi: 10.1016/j.mimet.2004.04.016
12. The European Committee on Antimicrobial Susceptibility Testing. EUCAST disk diffusion method, version 4.0, 2014. http://www.eucast.org.
13. The European Committee on Antimicrobial Susceptibility Testing. Routine internal quality control as recommended by EUCAST, version 3.1, 2013. http://www.eucast.org.
14. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved Standard-Tenth Edition. CLSI document M07-A10, 2015. Wayne, PA.
15. Carlton RM. Phage therapy: past history and future prospects. Arch Immunol Ther Exp (Warsz). 1999;47:267–274.
16. Demain AL, Sanchez S. Microbial drug discovery: 80 years of progress. J Antibiot (Tokyo). 2009;62:5–16. doi: 10.1038/ja.2008.16
17. Chen YL, Fang KC, Sheu JY, Hsu SL, Tzeng CC. Synthesis and antibacterial evaluation of certain quinolone derivatives. J Med Chem. 2001;44:2374–2377. doi: 10.1021/jm0100335
18. Foroumadi A, Soltani F, Moshafi MH, Ashraf-Askari R. Synthesis and in vitro antibacterial activity of some N-(5-aryl-1,3,4-thiadiazole-2-yl) piperazinyl quinolone derivatives. Farmaco. 2003;58:1023–1028. doi: 10.1016/S0014-827X(03)00191-5
19. Foroumadi A, Ghodsi S, Emami S, et al. Synthesis and antibacterial activity of new fluoroquinolones containing a substituted N-(phenethyl)piperazine moiety. Bioorg Med Chem Lett. 2006;16:3499–3503. doi: 10.1016/j.bmcl.2006.03.103
20. Wang S, Jia XD, Liu ML, Lu Y, Guo HY. Synthesis, antimycobacterial and antibacterial activity of ciprofloxacin derivatives containing a N-substituted benzyl moiety. Bioorg Med Chem Lett. 2012;22:5971–5975. doi: 10.1016/j.bmcl.2012.07.040
21. Abdelrahman MA, Salama I, Gomaa MS, Elaasser MM, Abdel-Aziz MM, Soliman DH. Design, synthesis and 2D QSAR study of novel pyridine and quinolone hydrazone derivatives as potential antimicrobial and antitubercular agents. Eur J Med Chem. 2018;138:698–714. doi: 10.1016/j.ejmech.2017.07.004
22. Wang LL, Battini N, Bheemanaboina RRY, Zhang SL, Zhou CH. Design and synthesis of aminothiazolyl norfloxacin analogues as potential antimicrobial agents and their biological evaluation. Eur J Med Chem. 2019;167:105–123. doi: 10.1016/j.ejmech.2019.01.072
23. Gonzalez JE, Keshavan ND. Messing with bacterial quorum sensing. Microbiol Mol Biol Rev. 2006;70:859–875. doi: 10.1128/MMBR.00002-06
24. Rasch M, Rasmussen TB, Andersen JB, et al. Well-known quorum sensing inhibitors do not affect bacterial quorum sensing-regulated bean sprout spoilage. J Appl Microbiol. 2007;102:826–837. doi: 10.1111/j.1365-2672.2006.03121.x
25. Truchado P, López-Gálvez F, Gil MI, Tomás-Barberán FA, Allende A. Quorum sensing inhibitory and antimicrobial activities of honeys and the relationship with individual phenolics. Food Chem. 2009;155:1337–1344. doi: 10.1016/j.foodchem.2009.01.065
26. Abudoleh SM, Mahasneh AM. Anti-quorum sensing activity of substances isolated from wild berry associated bacteria. Avicenna J Med Biotechnol. 2017;9:23–30.
27. Rasmussen TB, Skindersoe ME, Bjarnsholt T et al. Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiol. 2005;151:1325–1340. doi: 10.1099/mic.0.27715-0
28. Skindersoe ME, Alhede M, Phipps R, et al. Effects of antibiotics on quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2008;52:3648–3663. doi: 10.1128/AAC.01230-07