Effect of supplementation on biofilms and antibiotic efficacy against Pseudomonas aeruginosa
Abstract
Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen, is one of the leading causes of nosocomial infections, particularly in vulnerable patients. However, treating these infections is challenging due to its various antibiotic resistance mechanisms and biofilm formation ability. As traditional antibiotic development struggles to keep pace with evolving resistance, this review explores a promising alternative strategy which is enhancing existing antibiotic efficacy by combining them with nutritional supplements that modulate P. aeruginosa physiology. Specifically, it focuses on studies investigating the effects of diverse carbon, nitrogen, and iron sources on bacterial response to antibiotics, and the mechanisms underlying observed synergy. To achieve this, published literature on P. aeruginosa metabolism, antibiotic resistance, and nutritional influences was comprehensively analyzed and summarized. The findings highlight specific carbon, nitrogen, and iron sources that can enhance various antibiotic classes against P. aeruginosa. These include supplements capable of disrupting biofilm formation, reducing efflux pump activity, or interfering with other resistance mechanisms, thereby increasing antibiotic susceptibility. The specific mechanisms by which these supplements interact with bacterial physiology and antibiotic action are thoroughly discussed. Ultimately, modulating P. aeruginosa physiology through strategic supplementation alongside existing antibiotics offers a promising approach to overcome drug resistance in this pathogen.
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15. Sadeghi S, Faramarzi MA, Siroosi M. Design of novel human Microbiome-Derived Peptides for inhibition of OXA-48 Carbapenemase: an in-silico and in-vitro approach. Microb Pathog 2025; 206: 107779.
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3. Hancock RE, Speert DP. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and impact on treatment. Drug Resist Updat 2000; 3: 247-255.
4. Breidenstein EB, de la Fuente-Nunez C, Hancock RE. Pseudomonas aeruginosa: all roads lead to resistance. Trends Microbiol 2011; 19: 419-426.
5. Drenkard E. Antimicrobial resistance of Pseudomonas aeruginosa biofilms. Microbes Infect 2003; 5: 1213-1219.
6. Thi MTT, Wibowo D, Rehm BHA. Pseudomonas aeruginosa biofilms. Int J Mol Sci 2020; 21: 8671.
7. Keren I, Kaldalu N, Spoering A, Wang Y, Lewis K. Persister cells and tolerance to antimicrobials. FEMS Microbiol Lett 2004; 230: 13-18.
8. Rather MA, Gupta K, Mandal M. Microbial biofilm: formation, architecture, antibiotic resistance, and control strategies. Braz J Microbiol 2021; 52: 1701-1718.
9. Toyofuku M, Inaba T, Kiyokawa T, Obana N, Yawata Y, Nomura N. Environmental factors that shape biofilm formation. Biosci Biotechnol Biochem 2016; 80: 7-12.
10. Kunz Coyne AJ, El Ghali A, Holger D, Rebold N, Rybak MJ. Therapeutic strategies for emerging Multidrug-Resistant Pseudomonas aeruginosa. Infect Dis Ther 2022; 11: 661-682.
11. Chirgwin ME, Dedloff MR, Holban AM, Gestal MC. Novel therapeutic strategies applied to Pseudomonas aeruginosa infections in cystic fibrosis. Materials (Basel) 2019; 12: 4093.
12. Döring G, Pier GB. Vaccines and immunotherapy against Pseudomonas aeruginosa. Vaccine 2008; 26: 1011-1024.
13. Shao X, Xie Y, Zhang Y, Liu J, Ding Y, Wu M, et al. Novel therapeutic strategies for treating Pseudomonas aeruginosa infection. Expert Opin Drug Discov 2020; 15: 1403-1423.
14. Park S-C, Park Y, Hahm K-S. The role of antimicrobial peptides in preventing multidrug-resistant bacterial infections and biofilm formation. Int J Mol Sci 2011; 12: 5971-5992.
15. Sadeghi S, Faramarzi MA, Siroosi M. Design of novel human Microbiome-Derived Peptides for inhibition of OXA-48 Carbapenemase: an in-silico and in-vitro approach. Microb Pathog 2025; 206: 107779.
16. Sanya DRA, Onesime D, Vizzarro G, Jacquier N. Recent advances in therapeutic targets identification and development of treatment strategies towards Pseudomonas aeruginosa infections. BMC Microbiol 2023; 23: 86.
17. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 2002; 15: 167-193.
18. Alipour M, Suntres ZE, Omri A. Importance of DNase and alginate lyase for enhancing free and liposome encapsulated aminoglycoside activity against Pseudomonas aeruginosa. J Antimicrob Chemother 2009; 64: 317-325.
19. Bandara HM, Nguyen D, Mogarala S, Osinski M, Smyth HD. Magnetic fields suppress Pseudomonas aeruginosa biofilms and enhance ciprofloxacin activity. Biofouling 2015; 31: 443-457.
20. Bandara HM, Harb A, Kolacny D Jr, Martins P, Smyth HD. Sound waves effectively assist tobramycin in elimination of Pseudomonas aeruginosa biofilms in vitro. AAPS PharmSciTech 2014; 15: 1644-1654.
21. Street CN, Gibbs A, Pedigo L, Andersen D, Loebel NG. In vitro photodynamic eradication of Pseudomonas aeruginosa in planktonic and biofilm culture. Photochem Photobiol 2009; 85: 137-143.
22. Hoiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 2010; 35: 322-332.
23. Allison KR, Brynildsen MP, Collins JJ. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 2011; 473: 216-220.
24. Barraud N, Buson A, Jarolimek W, Rice SA. Mannitol enhances antibiotic sensitivity of persister bacteria in Pseudomonas aeruginosa biofilms. PLoS One 2013; 8(12): e84220.
25. Conrad RS, Wulf RG, Clay DL. Effects of carbon sources on antibiotic resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1979; 15: 59-66.
26. Chen M, Zhang W, Wu H, Guang C, Mu W. Mannitol: physiological functionalities, determination methods, biotechnological production, and applications. Appl Microbiol Biotechnol 2020; 104: 6941-6951.
27. Moore JE, Rendall JC, Downey DG. Pseudomonas aeruginosa displays an altered phenotype in vitro when grown in the presence of mannitol. Br J Biomed Sci 2015; 72: 115-119.
28. Ziemyte M, Carda-Dieguez M, Rodriguez-Diaz JC, Ventero MP, Mira A, Ferrer MD. Real-time monitoring of Pseudomonas aeruginosa biofilm growth dynamics and persister cells' eradication. Emerg Microbes Infect 2021; 10: 2062-2075.
29. Price KE, Orazi G, Ruoff KL, Hebert WP, O'Toole GA, Mastoridis P. Mannitol does not enhance tobramycin killing of Pseudomonas aeruginosa in a cystic fibrosis model system of bofilm formation. PLoS One 2015; 10(10): e0141192.
30. Yang Y, Tsifansky MD, Shin S, Lin Q, Yeo Y. Mannitol-guided delivery of Ciprofloxacin in artificial cystic fibrosis mucus model. Biotechnol Bioeng 2011; 108: 1441-1449.
31. Nevitt SJ, Thornton J, Murray CS, Dwyer T. Inhaled mannitol for cystic fibrosis. Cochrane Database Syst Rev 2020; 5: CD008649.
32. Zabner J, Seiler MP, Launspach JL, Karp PH, Kearney WR, Look DC, et al. The osmolyte xylitol reduces the salt concentration of airway surface liquid and may enhance bacterial killing. Proc Natl Acad Sci U S A 2000; 97: 11614-11619.
33. Gasmi Benahmed A, Gasmi A, Arshad M, Shanaida M, Lysiuk R, Peana M, et al. Health benefits of xylitol. Appl Microbiol Biotechnol 2020; 104: 7225-7237.
34. Santi E, Facchin G, Faccio R, Barroso R, Costa-Filho AJd, Borthagaray G, Torre M. Antimicrobial evaluation of new metallic complexes with xylitol active against P. aeruginosa and C. albicans: MIC determination, post-agent effect and Zn-uptake. J Inorg Biochem 2016; 155: 67-75.
35. Ruby JD, Momeni SS, Wu H. The effect of allulose, sucralose, and xylitol on Streptococcus mutans acid production. JADA Found Sci 2025; 4: 100052.
36. da Silva BP, de Lima Miguel R, Miletti LC, de Quadros RM. Inhibitory effects of EDTA, farnesol, and xylitol on biofilms produced by Staphylococcus aureus and Pseudomonas aeruginosa. Microbe 2025; 7: 100321.
37. Siroosi M, Jabalameli F. Effect of Xylitol on inhibition and eradication of Pseudomonas aeruginosa PAO1 and Methicillin-Resistant Staphylococcus aureus biofilms in an alginate bead model. Curr Microbiol 2024; 81: 272.
38. Zhou G, Peng H, Wang YS, Huang XM, Xie XB, Shi QS. Enhanced synergistic effects of xylitol and isothiazolones for inhibition of initial biofilm formation by Pseudomonas aeruginosa ATCC 9027 and Staphylococcus aureus ATCC 6538. J Oral Sci 2019; 61: 255-263.
39. Dowd SE, Sun Y, Smith E, Kennedy JP, Jones CE, Wolcott R. Effects of biofilm treatments on the multi-species Lubbock chronic wound biofilm model. J Wound Care 2009; 18: 508, 510-512.
40. Sousa LPd, Farah DA, Calil NO, Oliveira MG, Silva SS, Raposo NRB. In vitro inhibition of Pseudomonas aeruginosa adhesion by Xylitol. Braz Arch Biol Technol 2011; 54: 877-884.
41. Ng SF, Leow HL. Development of biofilm-targeted antimicrobial wound dressing for the treatment of chronic wound infections. Drug Dev Ind Pharm 2015; 41: 1902-1909.
42. Ammons MC, Ward LS, James GA. Anti-biofilm efficacy of a lactoferrin/xylitol wound hydrogel used in combination with silver wound dressings. Int Wound J 2011; 8: 268-273.
43. Durairaj L, Launspach J, Watt JL, Mohamad Z, Kline J, Zabner J. Safety assessment of inhaled xylitol in subjects with cystic fibrosis. J Cyst Fibros 2007; 6: 31-34.
44. Kim BH, Gadd GM (2008). Bacterial Physiology and Metabolism: Cambridge University Press.
45. Chen T, Xu Y, Xu W, Liao W, Xu C, Zhang X, et al. Hypertonic glucose inhibits growth and attenuates virulence factors of multidrug-resistant Pseudomonas aeruginosa. BMC Microbiol 2020; 20: 203.
46. Szilagyi A (2019). Digestion, absorption, metabolism and physiological effects of lactose. In Lactose, Evolutionary role, Health effects, and Applications. Paques M & Lidner C eds: Academic Press, Elsevier, London UK.
47. Nelson RK, Poroyko V, Morowitz MJ, Liu D, Alverdy JC. Effect of dietary monosaccharides on Pseudomonas aeruginosa virulence. Surg Infect (Larchmt) 2013; 14: 35-42.
48. Grishin AV, Krivozubov MS, Karyagina AS, Gintsburg AL. Pseudomonas aeruginosa lectins as targets for novel antibacterials. Acta Naturae 2015; 7: 29-41.
49. von Bismarck Pv, Schneppenheim R, Schumacher U. Successful treatment of Pseudomonas aeruginosa respiratory tract infection with a sugar solution--a case report on a lectin based therapeutic principle. Klin Padiatr 2001; 213: 285-287.
50. Hauber HP, Schulz M, Pforte A, Mack D, Zabel P, Schumacher U. Inhalation with fucose and galactose for treatment of Pseudomonas aeruginosa in cystic fibrosis patients. Int J Med Sci 2008; 5: 371-376.
51. Sauer K, Cullen MC, Rickard AH, Zeef LA, Davies DG, Gilbert P. Characterization of nutrient-induced dispersion in Pseudomonas aeruginosa PAO1 biofilm. J Bacteriol 2004; 186: 7312-7326.
52. Sauvage S, Gaviard C, Tahrioui A, Coquet L, Le H, Alexandre S, et al. Impact of carbon source Supplementations on Pseudomonas aeruginosa physiology. J Proteome Res 2022; 21: 1392-1407.
53. Sommerfeld Ross S, Fiegel J. Nutrient dispersion enhances conventional antibiotic activity against Pseudomonas aeruginosa biofilms. Int J Antimicrob Agents 2012; 40: 177-181.
54. Giorgi-Coll S, Amaral AI, Hutchinson PJA, Kotter MR, Carpenter KLH. Succinate supplementation improves metabolic performance of mixed glial cell cultures with mitochondrial dysfunction. Sci Rep 2017; 7: 1003.
55. Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr 2009; 90: 1-10.
56. Hassett DJ, Cuppoletti J, Trapnell B, Lymar SV, Rowe JJ, Yoon SS, et al. Anaerobic metabolism and quorum sensing by Pseudomonas aeruginosa biofilms in chronically infected cystic fibrosis airways: rethinking antibiotic treatment strategies and drug targets. Adv Drug Deliv Rev 2002; 54: 1425-1443.
57. Martin LW, Gray AR, Brockway B, Lamont IL. Pseudomonas aeruginosa is oxygen-deprived during infection in cystic fibrosis lungs, reducing the effectiveness of antibiotics. FEMS Microbiol Lett 2023; 370: fnad076.
58. Palmer KL, Brown SA, Whiteley M. Membrane-bound nitrate reductase is required for anaerobic growth in cystic fibrosis sputum. J Bacteriol 2007; 189: 4449-4455.
59. Borriello G, Richards L, Ehrlich GD, Stewart PS. Arginine or nitrate enhances antibiotic susceptibility of Pseudomonas aeruginosa in biofilms. Antimicrob Agents Chemother 2006; 50: 382-384.
60. Borriello G, Werner E, Roe F, Kim AM, Ehrlich GD, Stewart PS. Oxygen limitation contributes to antibiotic tolerance of Pseudomonas aeruginosa in biofilms. Antimicrob Agents Chemother 2004; 48: 2659-2664.
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| Files | ||
| Issue | Vol 17 No 6 (2025) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijm.v17i6.20353 | |
| Keywords | ||
| Pseudomonas aeruginosa Anti-bacterial agents Biofilms Persister cells Xylitol Arginine Iron | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Salehibarmi M, Siroosi M. Effect of supplementation on biofilms and antibiotic efficacy against Pseudomonas aeruginosa. Iran J Microbiol. 2025;17(6):861-874.
