Int J Antimicrob Agents

. 2021 Sep 18;106438.

doi: 10.1016/j.ijantimicag.2021.106438. Online ahead of print.

Effect of iron chelation on anti-pseudomonal activity of doxycycline

M E Faure ¹, A Cilibrizzi ¹, V Abbate ², K D Bruce ¹, R C Hider ³

Affiliations expand

• PMID: 34547423

DOI: 10.1016/j.ijantimicag.2021.106438

Abstract

Background: There is growing concern regarding the lack of novel antimicrobial agents and increasing resistance of microorganisms to existing agents. This has stimulated the exploration of novel strategies for infection treatment.

Objective: To investigate synergistic interactions between five tetracyclines and tobramycin with an iron chelator (CP762) against two reference strains and nine clinical isolates of Pseudomonas aeruginosa from cystic fibrosis patients.

Method: Microdilution assays for minimal inhibitory concentration determination and checkerboard assays were used to assess synergy between antibiotics and CP762. Given the iron binding capacity of tetracyclines, the binding of iron with doxycycline was investigated using Job's plot methodology. The iron bound form of doxycycline was compared with the unbound agent in terms of the synergy observed. Enhancement of doxycycline anti-biofilm activity was also assessed.

Results: Synergistic activity with CP762 was evident for all tetracyclines, except minocycline, against the reference strains but activity against clinical isolates was variable. Synergy was not demonstrated for tobramycin against any of the strains tested. This led to the hypothesis that iron chelation preserves the binding nature of tetracyclines to the bacterial ribosome. Susceptibility to iron bound doxycycline was decreased by two to four-fold and synergistic interactions with the iron chelator were consistently found to be more intense with iron-bound doxycycline than with the antibiotic alone. The doxycycline - iron chelator combination also significantly reduced cell viability in established biofilms.

Conclusion: The data in this study provides evidence that iron chelation enhances the anti-pseudomonal activity of tetracyclines, and more specifically, of doxycycline.

Curr Med Chem

. 2021;28(7):1407-1421.

doi: 10.2174/0929867327666200510235512.

Biotechnological Potential of Streptomyces Siderophores as New Antibiotics

Luciana Terra ¹, Norman Ratcliffe ¹, Helena Carla Castro ¹, Ana Carolina Paulo Vicente ², Paul Dyson ³

Affiliations expand

• PMID: 32389112

DOI: 10.2174/0929867327666200510235512

Abstract

Background: Siderophores are small-molecule iron-chelators produced by microorganisms and plants growing mostly under low iron conditions. Siderophores allow iron capture and transport through cell membranes into the cytoplasm, where iron is released for use in biological processes. These bacterial iron uptake systems can be used for antibiotic conjugation or as targets for killing pathogenic bacteria. Siderophores have been explored recently because of their potential applications in environmental and therapeutic research. They are present in Streptomyces, Grampositive bacteria that are an important source for discovering new siderophores.

Objective: This review summarizes siderophore molecules produced by the genus Streptomyces emphasizing their potential as biotechnological producers and also illustrating genomic tools for discovering siderophores useful for treating bacterial infections.

Methods: The literature search was performed using PUBMED and MEDLINE databases with keywords siderophore, secondary metabolites, Trojan horse strategy, sideromycin and Streptomyces. The literature research focused on bibliographic databases including all siderophores identified in the genus Streptomyces. In addition, reference genomes of Streptomyces from GenBank were used to identify siderophore biosynthetic gene clusters by using the antiSMASH platform.

Results: This review has highlighted some of the many siderophore molecules produced by Streptomyces, illustrating the diversity of their chemical structures and a wide spectrum of bioactivities against pathogenic bacteria. Furthermore, the possibility of using siderophores conjugated with antibiotics could be an alternative to overcome bacterial resistance to drugs and could improve their therapeutic efficacy.

Conclusion: This review confirms the importance of Streptomyces as a rich source of siderophores, and underlines their potential as antibacterial agents.