Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

In vitro antibacterial effects of combination of ciprofloxacin with compounds isolated from Streptomyces luteireticuli NIIST-D75

The Journal of Antibiotics volume 76, pages 198–210 (2023)Cite this article

Subjects

Abstract

Three phenazines, 1-methoxyphenazine (1), methyl-6-methoxyphenazine-1-carboxylate (2), 1,6-dimethoxyphenazine (4), and a 2,3-dimethoxy benzamide (3) were isolated from the Streptomyces luteireticuli NIIST-D75, and the antibacterial effects of compounds 1-3, each in combination with ciprofloxacin, were investigated. The in vitro antibacterial activity was assessed by microdilution, checkerboard, and time-kill assay against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi. According to the checkerboard assay results, each combination of compounds 1, 2 and 3 with ciprofloxacin resulted in a significantly lower minimum inhibitory concentrations (MICs) of 0.02–1.37 µg ml−1, suggesting synergistic combinations by fractional inhibitory concentration index, and displayed bactericidal activity in time-kill kinetics within 48 h. SEM analysis was carried out to determine the changes in morphology in S. aureus and E. coli during treatment with individual combination of ciprofloxacin and compounds (1-3), which revealed drastic changes in the cells such as dent formation, biofilm disruption, cell bursting, and doughnut-like formation, change in surface morphology in S. aureus, and cell elongation, cell burst with ruptured cell, and change in surface morphology in E. coli. Hep G2 cell viability was not affected by the compounds (1-3) that were tested for cytotoxicity up to 250 µM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Li X, He Y, Wang Z, Wei J, Hu T, Si J, et al. A combination therapy of phages and antibiotics: two is better than one. Int J Biol Sci. 2021;17:3573–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Namivandi-Zangeneh R, Wong EHH, Boyer C. Synthetic antimicrobial polymers in combination therapy: tackling antibiotic resistance. ACS Infect Dis. 2021;7:215–53.

    Article  CAS  PubMed  Google Scholar 

  3. Shaw E, Wuest WM. Virulence attenuating combination therapy: a potential multi-target synergy approach to treat Pseudomonas aeruginosa infections in cystic fibrosis patients. RSC Med Chem. 2020;11:358–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cheng Y-S, Williamson PR, Zheng W. Improving therapy of severe infections through drug repurposing of synergistic combinations. Curr Opin Pharm. 2019;48:92–8.

    Article  CAS  Google Scholar 

  5. Möhler JS, Sim W, Blaskovich MAT, Cooper MA, Ziora ZM. Silver bullets: a new lustre on an old antimicrobial agent. Biotechnol Adv. 2018;36:1391–411.

    Article  PubMed  Google Scholar 

  6. Ni W, Shao X, Di X, Cui J, Wang R, Liu Y. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: a systematic review and meta-analysis. Int J Antimicrob Agents. 2015;45:8–18.

    Article  CAS  PubMed  Google Scholar 

  7. Yap PSX, Yiap BC, Ping HC, Lim SHE. Essential Oils, a new horizon in combating bacterial antibiotic resistance. Open Microbiol J. 2014;8:6–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jackson J, Chen C, Buising K. Aminoglycosides. Curr Opin Infect Dis. 2013;26:516–25.

    Article  CAS  PubMed  Google Scholar 

  9. Liu Y, Li H, Zhang Y, Ye Y, Gao Y, Li J. In vitro and in vivo activity of ciprofloxacin/fosfomycin combination therapy against ciprofloxacin-resistant Shigella flexneri isolates. Infect Drug Resist. 2019;12:1619–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim SE, Kim HK, Choi S-M, Yu Y, Kim UJ, Darboe KS, et al. In vitro synergy and in vivo activity of tigecycline-ciprofloxacin combination therapy against vibrio vulnificus sepsis. Antimicrob Agents Chemother. 2019;63. https://doi.org/10.1128/AAC.00310-19.

  11. Elkhatib W, Noreddin A. Efficacy of ciprofloxacin-clarithromycin combination against drug-resistant pseudomonas aeruginosa mature biofilm using in vitro experimental model. Microb Drug Resistance. 2014;20:575–82.

    Article  CAS  Google Scholar 

  12. Siqueira VLD, Cardoso RF, Caleffi-Ferracioli KR, de Lima Scodro RB, Fernandez MA, Fiorini A, et al. Structural changes and differentially expressed genes in pseudomonas aeruginosa exposed to meropenem-ciprofloxacin combination. Antimicrob Agents Chemother. 2014;58:3957–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jang H-C, Choi S-M, Kim HK, Kim S-E, Kang S-J, Park K-H, et al. In vivo efficacy of the combination of ciprofloxacin and cefotaxime against vibrio vulnificus sepsis. PLoS One. 2014;9:e101118.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chang C-M, Lee H-C, Lee N-Y, Huang G-C, Lee I-W, Ko W-C. Cefotaxime-ciprofloxacin combination therapy for nontyphoid salmonella bacteremia and paravertebral abscess after failure of monotherapy. Pharmacotherapy. 2006;26:1671–4.

    Article  PubMed  Google Scholar 

  15. Beach JM, Champney WS. An examination of the inhibitory effects of three antibiotics in combination on ribosome biosynthesis in Staphylococcus aureus. Arch Microbiol. 2014;196:249–60.

    Article  CAS  PubMed  Google Scholar 

  16. Drago L, de Vecchi E, Nicola L, Legnani D, Lombardi A, Gismondo MR. In vitro synergy and selection of resistance by fluoroquinolones plus amikacin or β-lactams against extended-spectrum β-lactamase-producing Escherichia coli. J Chemother. 2005;17:46–53.

    Article  CAS  PubMed  Google Scholar 

  17. Brouqui P, Rousseau MC, Stein A, Drancourt M, Raoult D. Treatment of Pseudomonas aeruginosa-infected orthopedic prostheses with ceftazidime-ciprofloxacin antibiotic combination. Antimicrob Agents Chemother. 1995;39:2423–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dey R, Sultana S, Bishayi B. Combination treatment of celecoxib and ciprofloxacin attenuates live S. aureus induced oxidative damage and inflammation in murine microglia via regulation of cytokine balance. J Neuroimmunol. 2018;316:23–39.

    Article  CAS  PubMed  Google Scholar 

  19. Cho D-Y, Lim DJ, Mackey C, Skinner D, Zhang S, McCormick J, et al. Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, enhances ciprofloxacin activity against Pseudomonas aeruginosa. Am J Rhinol Allergy. 2019;33:129–36.

    Article  PubMed  Google Scholar 

  20. Soboh F, Khoury AE, Zamboni AC, Davidson D, Mittelman MW. Effects of ciprofloxacin and protamine sulfate combinations against catheter-associated Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother. 1995;39:1281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lu Q, Yu J, Bao L, Ran T, Zhong H. Effects of combined treatment with ambroxol and ciprofloxacin on catheter-associated pseudomonas aeruginosa biofilms in a rat model. Chemotherapy. 2013;59:51–6.

    Article  CAS  PubMed  Google Scholar 

  22. Kart D, Reçber T, Nemutlu E, Sagiroglu M. Sub-inhibitory concentrations of ciprofloxacin alone and combinations with plant-derived compounds against P. aeruginosa Biofilms and their effects on the metabolomic profile of P. aeruginosa Biofilms. Antibiotics. 2021;10:414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lin Y, Quan D, Chang RYK, Chow MYT, Wang Y, Li M, et al. Synergistic activity of phage PEV20-ciprofloxacin combination powder formulation—A proof-of-principle study in a P. aeruginosa lung infection model. Eur J Pharm Biopharm. 2021;158:166–71.

    Article  CAS  PubMed  Google Scholar 

  24. Mohamed SH, Mohamed MSM, Khalil MS, Azmy M, Mabrouk MI. Combination of essential oil and ciprofloxacin to inhibit/eradicate biofilms in multidrug-resistant Klebsiella pneumoniae. J Appl Microbiol. 2018;125:84–95.

    Article  CAS  PubMed  Google Scholar 

  25. Zhou X-Y, Ye X-G, He L-T, Zhang S-R, Wang R-L, Zhou J, et al. In vitro characterization and inhibition of the interaction between ciprofloxacin and berberine against multidrug-resistant Klebsiella pneumonia e. J Antibiot (Tokyo). 2016;69:741–6.

    Article  CAS  PubMed  Google Scholar 

  26. Chan BCL, Ip M, Lau CBS, Lui SL, Jolivalt C, Ganem-Elbaz C, et al. Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase. J Ethnopharmacol. 2011;137:767–73.

    Article  CAS  PubMed  Google Scholar 

  27. Dey D, Debnath S, Hazra S, Ghosh S, Ray R, Hazra B. Pomegranate pericarp extract enhances the antibacterial activity of ciprofloxacin against extended-spectrum β-lactamase (ESBL) and metallo-β-lactamase (MBL) producing Gram-negative bacilli. Food Chem Toxicol. 2012;50:4302–9.

    Article  CAS  PubMed  Google Scholar 

  28. Arora S, Baptista C, Lim CS. Maggot metabolites and their combinatory effects with antibiotic on Staphylococcus aureus. Ann Clin Microbiol Antimicrob. 2011;10:6.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tambat R, Jangra M, Mahey N, Chandal N, Kaur M, Chaudhary S, et al. Microbe-derived indole metabolite demonstrates potent multidrug efflux pump inhibition in staphylococcus aureus. Front Microbiol. 2019;10. https://doi.org/10.3389/fmicb.2019.02153.

  30. Genilloud O. Mining actinomycetes for novel antibiotics in the omics era: are we ready to exploit this new paradigm? Antibiotics. 2018;7:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nampoothiri KM, Ramkumar B, Pandey A. Western ghats of india: rich source of microbial biodiversity. J Sci Ind Res (India). 2013;72:617–23.

    Google Scholar 

  32. Vasava ZT, Mistry KJ, Patel PP, Markande AR. Exploring microbial bioactive molecules from Western Ghats, India. Acta Ecologica Sinica. 2021. https://doi.org/10.1016/j.chnaes.2021.09.011.

  33. Drissya T, Induja DK, Poornima MS, Jesmina ARS, Prabha B, Saumini M, et al. A novel aureothin diepoxide derivative from Streptomyces sp. NIIST-D31 strain. J Antibiot (Tokyo). 2022. https://doi.org/10.1038/s41429-022-00547-1.

  34. CLSI. Performance standards for antimicrobial disk susceptibility tests; approved standard- Eleventh edition. CLSI document M02-A11 29. 2012;1–54.

  35. Fadwa AO, Alkoblan DK, Mateen A, Albarag AM. Synergistic effects of zinc oxide nanoparticles and various antibiotics combination against pseudomonas aeruginosa clinically isolated bacterial strains. Saudi J Biol Sci. 2021;28:928–35.

    Article  CAS  PubMed  Google Scholar 

  36. Kumar SN, Lankalapalli RS, Kumar BSD. In vitro antibacterial screening of six proline-based cyclic dipeptides in combination with β-lactam antibiotics against medically important bacteria. Appl Biochem Biotechnol. 2014;173:116–28.

    Article  CAS  PubMed  Google Scholar 

  37. Mal A, Vijayakumar S, Mishra RK, Jacob J, Pillai RS, Dileep Kumar BS, et al. Supramolecular surface charge regulation in ionic covalent organic nanosheets: reversible exfoliation and controlled bacterial growth. Angew Chem - Int Ed. 2020;59:8713–9.

    Article  CAS  Google Scholar 

  38. Jacob J, Rajendran RU, Priya SH, Purushothaman J, Saraswathy Amma DKBN. Enhanced antibacterial metabolite production through the application of statistical methodologies by a Streptomyces nogalater NIIST A30 isolated from Western Ghats forest soil. PLoS One. 2017;12:1–21.

    Article  Google Scholar 

  39. Bauer AW, Kirby WM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966;45:493–6.

    Article  CAS  PubMed  Google Scholar 

  40. Anupama N, Preetha Rani MR, Shyni GL, Raghu KG. Glucotoxicity results in apoptosis in H9c2 cells via alteration in redox homeostasis linked mitochondrial dynamics and polyol pathway and possible reversal with cinnamic acid. Toxicol Vitr. 2018;53:178–92.

    Article  CAS  Google Scholar 

  41. Yamanaka S. Mycological studies on Streptomyces luteoreticuli and the isolation of two antibiotics, mycomethoxin A and B. Chiba Igakkai Zasshi. 1972;48:63–73.

    CAS  Google Scholar 

  42. Yamagishi S, Koyama Y, Fukakusa Y, Kyomura N, Ohishi J-I, Hamamichi N, et al. On the metabolites of streptomyces luteoreticuli KATOH et ARAI. I.: isolation of the metabolites. Yakugaku Zasshi. 1971;91:351–7.

    Article  CAS  PubMed  Google Scholar 

  43. Shaaban KA, Shepherd MD, Ahmed TA, Nybo SE, Leggas M, Rohr J. Pyramidamycins A-D and 3-hydroxyquinoline-2-carboxamide; cytotoxic benzamides from streptomyces sp. DGC1. J Antibiot (Tokyo). 2012;65:615–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang X, Peng T, Yang Y, Li W, Xiong J, Zhao L, et al. Antimicrobial and antioxidant activities of a new benzamide from endophytic Streptomyces sp. YIM 67086. Nat Prod Res. 2015;29:331–5.

    Article  CAS  PubMed  Google Scholar 

  45. Nishanth Kumar S, Nisha GV, Sudaresan A, Venugopal VV, Sree Kumar MM, Lankalapalli RS, et al. Synergistic activity of phenazines isolated from Pseudomonas aeruginosa in combination with azoles against Candida species. Med Mycol. 2014;52:482–90.

    Article  CAS  PubMed  Google Scholar 

  46. Chan BCL, Ip M, Lau CBS, Lui SL, Jolivalt C, Ganem-Elbaz C, et al. Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase. J Ethnopharmacol. 2011;137:767–73.

    Article  CAS  PubMed  Google Scholar 

  47. Kim D-M, Neupane GP, Jang SJ, Kim SH, Lee BK. In vitro efficacy of the combination of ciprofloxacin and cefotaxime against nalidixic acid-resistant Salmonella enterica serotype Typhi. Int J Antimicrob Agents. 2010;36:155–8.

    Article  CAS  PubMed  Google Scholar 

  48. Mossine VV, Chance DL, Waters JK, Mawhinney TP. Interaction of bacterial phenazines with colistimethate in bronchial epithelial cells. Antimicrob Agents Chemother. 2018;62. https://doi.org/10.1128/AAC.02349-17.

  49. Qian W, Liu M, Fu Y, Zhang J, Liu W, Li J, et al. Antimicrobial mechanism of luteolin against Staphylococcus aureus and Listeria monocytogenes and its antibiofilm properties. Micro Pathog. 2020;142:104056.

    Article  CAS  Google Scholar 

  50. Hartmann M, Berditsch M, Hawecker J, Ardakani MF, Gerthsen D, Ulrich AS. Damage of the bacterial cell envelope by antimicrobial peptides gramicidin S and PGLa as revealed by transmission and scanning electron microscopy. Antimicrob Agents Chemother. 2010;54:3132–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang X, Sun X, Wu J, Wu Y, Wang Y, Hu X, et al. Berberine Damages the Cell Surface of Methicillin-Resistant Staphylococcus aureus. Front Microbiol. 2020;11. https://doi.org/10.3389/fmicb.2020.00621.

  52. Akbari R, Hakemi Vala M, Hashemi A, Aghazadeh H, Sabatier JM, Pooshang Bagheri K. Action mechanism of melittin-derived antimicrobial peptides, MDP1 and MDP2, de novo designed against multidrug resistant bacteria. Amino Acids. 2018;50:1231–43.

    Article  CAS  PubMed  Google Scholar 

  53. Sarkar P, Acharyya S, Banerjee A, Patra A, Thankamani K, Koley H, et al. Intracellular, biofilm-inhibitory and membrane-damaging activities of nimbolide isolated from Azadirachta indica A. Juss (Meliaceae) against meticillin-resistant Staphylococcus aureus. J Med Microbiol. 2016;65:1205–14.

    Article  CAS  PubMed  Google Scholar 

  54. Becerra MC, Páez PL, Laróvere LE, Albesa I. Lipids and DNA oxidation in Staphylococcus aureus as a consequence of oxidative stress generated by ciprofloxacin. Mol Cell Biochem. 2006;285:29–34.

    Article  CAS  PubMed  Google Scholar 

  55. Diver JM, Wise R. Morphological and biochemical changes in Escherichia coli after exposure to ciprofloxacin. J Antimicrob Chemother. 1986;18:31–41.

    Article  CAS  PubMed  Google Scholar 

  56. Sun Y, Zhang Z, Wang S. Study on the bactericidal mechanism of atmospheric-pressure low-temperature plasma against escherichia coli and its application in fresh-cut cucumbers. Molecules. 2018;23:975.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

A.R.S.J., D.K.I., T.D., C.R.S. are thankful to UGC and CSIR for the fellowship.

Author information

Authors and Affiliations

  1. Agro-Processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, 695019, India

    Abdul Rasheed Safiya Jesmina, Thankappan Drissya, Chakiniplackal Rajan Sruthi, Kozhiparambil Gopalan Raghu & Bhaskaran Nair Saraswathy Amma Dileep Kumar

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Abdul Rasheed Safiya Jesmina, D. K. Induja, Thankappan Drissya, Chakiniplackal Rajan Sruthi, Kozhiparambil Gopalan Raghu, Bhaskaran Nair Saraswathy Amma Dileep Kumar & Ravi S. Lankalapalli

  3. Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, 695019, India

    D. K. Induja & Ravi S. Lankalapalli

  4. Transdisciplinary Biology, Bioinformatics Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, India

    Shijulal Nelson-Sathi

Authors
  1. Abdul Rasheed Safiya Jesmina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. K. Induja
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thankappan Drissya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chakiniplackal Rajan Sruthi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kozhiparambil Gopalan Raghu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shijulal Nelson-Sathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bhaskaran Nair Saraswathy Amma Dileep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ravi S. Lankalapalli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Bhaskaran Nair Saraswathy Amma Dileep Kumar or Ravi S. Lankalapalli.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

41429_2023_600_MOESM1_ESM.docx

In vitro antibacterial effects of combination of ciprofloxacin with compounds isolated from Streptomyces luteireticuli NIIST-D75

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jesmina, A.R.S., Induja, D.K., Drissya, T. et al. In vitro antibacterial effects of combination of ciprofloxacin with compounds isolated from Streptomyces luteireticuli NIIST-D75. J Antibiot 76, 198–210 (2023). https://doi.org/10.1038/s41429-023-00600-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-023-00600-7

This article is cited by

Search

Advanced search

Quick links