Tehran University of Medical Sciences Iranian Journal of Microbiology 2008-3289 17 6 2025 12 13 861 874 Mana Salehibarmi Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Maryam Siroosi Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 2025 01 30 2025 08 14 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. https://ijm.tums.ac.ir/index.php/ijm/article/view/5270 https://ijm.tums.ac.ir/index.php/ijm/article/download/5270/1833