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Volume 12
Issue 8
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Article

Exploring Antibiotic-Potentiating Effects of Tobramycin–Deferiprone Conjugates in Pseudomonas aeruginosa

by
Karan Gandhi
1,
Shiv Dhiman
1,
Rajat Arora
1,
Danzel Marie Ramirez
1,
Danyel Ramirez
1,
Gilbert Arthur
2 and
Frank Schweizer
1,3,*
1
Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
2
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
3
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3R 0J9, Canada
*
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(8), 1261; https://doi.org/10.3390/antibiotics12081261
Submission received: 12 July 2023 / Revised: 26 July 2023 / Accepted: 27 July 2023 / Published: 31 July 2023
(This article belongs to the Special Issue Antimicrobial Chemotherapy: New Therapeutic Approaches against the Drug-Resistant and Difficult to Treat Bacterial Infections)
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Abstract

Metal ions, including Fe3+, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including Pseudomonas aeruginosa. To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of P. aeruginosa. While all TOB-DEF conjugates were inactive against P. aeruginosa, the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, 1c containing a C12 tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant P. aeruginosa isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe3+ concentration.
Keywords: antibacterial activity; antibiotic potentiation; tobramycin-deferiprone conjugates; Pseudomonas aeruginosa antibacterial activity; antibiotic potentiation; tobramycin-deferiprone conjugates; Pseudomonas aeruginosa
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MDPI and ACS Style

Gandhi, K.; Dhiman, S.; Arora, R.; Ramirez, D.M.; Ramirez, D.; Arthur, G.; Schweizer, F. Exploring Antibiotic-Potentiating Effects of Tobramycin–Deferiprone Conjugates in Pseudomonas aeruginosa. Antibiotics 2023, 12, 1261. https://doi.org/10.3390/antibiotics12081261

AMA Style

Gandhi K, Dhiman S, Arora R, Ramirez DM, Ramirez D, Arthur G, Schweizer F. Exploring Antibiotic-Potentiating Effects of Tobramycin–Deferiprone Conjugates in Pseudomonas aeruginosa. Antibiotics. 2023; 12(8):1261. https://doi.org/10.3390/antibiotics12081261

Chicago/Turabian Style

Gandhi, Karan, Shiv Dhiman, Rajat Arora, Danzel Marie Ramirez, Danyel Ramirez, Gilbert Arthur, and Frank Schweizer. 2023. "Exploring Antibiotic-Potentiating Effects of Tobramycin–Deferiprone Conjugates in Pseudomonas aeruginosa" Antibiotics 12, no. 8: 1261. https://doi.org/10.3390/antibiotics12081261

APA Style

Gandhi, K., Dhiman, S., Arora, R., Ramirez, D. M., Ramirez, D., Arthur, G., & Schweizer, F. (2023). Exploring Antibiotic-Potentiating Effects of Tobramycin–Deferiprone Conjugates in Pseudomonas aeruginosa. Antibiotics, 12(8), 1261. https://doi.org/10.3390/antibiotics12081261

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