Design and synthesis of new polyamine quinoline antibiotic enhancers to fight resistant gram-negative P. aeruginosa bacteria

Troia, Thomas; Siad, Jacques; Giorgio, Carole Di; Brunel, Jean‐Michel

doi:10.1016/j.ejmcr.2022.100054

Cited by 6 publications

(6 citation statements)

References 19 publications

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“…The literature reports that simple unsubstituted polyamines, spermine and spermidine, can act synergistically with a number of antibiotics [ 60 , 61 ]. Moreover, recent studies of natural or synthetic products containing polyamines have shown that molecules, such as squalamine [ 62 ], motuporamine MOTUN44 [ 63 ], ianthelliformisamine [ 64 ], 6-bromoindolglyoxamide [ 65 ], and polyaminoisoprenoid NV716 [ 66 , 67 ], possess both an antimicrobial effect and the ability to enhance the activity of antibiotics by increasing membrane permeability and/or membrane depolarization [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds

et al. 2023

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Fusidic acid (FA) is an antibiotic with high activity against Staphylococcus aureus; it has been used in clinical practice since the 1960s. However, the narrow antimicrobial spectrum of FA limits its application in the treatment of bacterial infections. In this regard, this work aims both at the study of the antimicrobial effect of a number of FA amines and at the identification of their potential biological targets. In this way, FA analogues containing aliphatic and aromatic amino groups and biogenic polyamine, spermine and spermidine, moieties at the C-3 atom, were synthesized (20 examples). Pyrazinecarboxamide-substituted analogues exhibit a high antibacterial activity against S. aureus (MRSA) with MIC ≤ 0.25 μg/mL. Spermine and spermidine derivatives, along with activity against S. aureus, also inhibit the growth and reproduction of Gram-negative bacteria Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa, and have a high fungicidal effect against Candida albicans and Cryptococcus neoformans. The study of the membrane activity demonstrated that the spermidine- and spermine-containing compounds are able to immerse into membranes and disorder the lipidsleading to a detergent effect. Moreover, spermine-based compounds are also able to form ion-permeable pores in the lipid bilayers mimicking the bacterial membranes. Using molecular docking, inhibition of the protein synthesis elongation factor EF-G was proposed, and polyamine substituents were shown to make the greatest contribution to the stability of the complexes of fusidic acid derivatives with biological targets. This suggests that the antibacterial effect of the obtained compounds may be associated with both membrane activity and inhibition of the elongation factor EF-G.

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Section: Discussionmentioning

confidence: 99%

3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds

et al. 2023

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“…Of note was the identification of antibiotic enhancing analogues whose cytotoxicity ranged from negligible to significant. The mechanism of action of two of the best compounds was studied against P. aeruginosa and S. aureus establishing a different behavior towards integrity or depolarization of bacterial membranes depending on the structure of the considered polyamine quinoline derivatives [113]. The lack of novel drugs in development and the combination of increased incidence of drug-resistant strains of bacteria has created the need for the search for new antimicrobials, as well as new original strategies, to fight bacterial resistance.…”

Section: Synthesis and Sar Study Of New 5-and 7-substituted 3-nitroim...mentioning

confidence: 99%

“…Of note was the identification of antibiotic enhancing analogues whose cytotoxicity ranged from negligible to significant. The mechanism of action of two of the best compounds was studied against P. aeruginosa and S. aureus establishing a different behavior towards integrity or depolarization of bacterial membranes depending on the structure of the considered polyamine quinoline derivatives [113]. compounds analogs (series A to G) of the first identified bioactive phenanthroline hits (Figure 32) [115].…”

Section: Synthesis and Sar Study Of New 5-and 7-substituted 3-nitroim...mentioning

confidence: 99%

31st Annual GP2A Medicinal Chemistry Conference

Primas,

Castera-Ducros,

Paoli-Lombardo

et al. 2024

DDC

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The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP2A) held its 31st annual conference in August 2023 at the Faculty of Pharmacy of Aix-Marseille University, Marseille, France. There were 8 keynote presentations, 10 early career researcher oral presentations and 23 poster presentations. Among them, four awards were delivered, two for best oral communications and two for the best poster presentations.

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“…The two quinoline polyamine derivatives 19 and 20 are used as an adjuvant for doxycycline by improving its activity against P. aeruginosa . A disruption of integrity and depolarization of bacterial membranes have been observed with derivative 20, while the mechanism of action of derivative 19 is not yet known [ 95 ]. The polyamine farnesyl 21 to 24 derivatives make the bacterium P. aeruginosa sensitive to the antibiotic tetracycline, and this is linked to the hydrophobicity of the antibiotic and to the alteration of the integrity of the bacterial outer membrane [ 96 , 97 ].…”

Section: Outer Membrane Permeabilizationmentioning

confidence: 99%

Rejuvenating the Activity of Usual Antibiotics on Resistant Gram-Negative Bacteria: Recent Issues and Perspectives

Tabcheh

Vergalli

Davin-Régli

et al. 2023

IJMS

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Antibiotic resistance continues to evolve and spread beyond all boundaries, resulting in an increase in morbidity and mortality for non-curable infectious diseases. Due to the failure of conventional antimicrobial therapy and the lack of introduction of a novel class of antibiotics, novel strategies have recently emerged to combat these multidrug-resistant infectious microorganisms. In this review, we highlight the development of effective antibiotic combinations and of antibiotics with non-antibiotic activity-enhancing compounds to address the widespread emergence of antibiotic-resistant strains.

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Design and synthesis of new polyamine quinoline antibiotic enhancers to fight resistant gram-negative P. aeruginosa bacteria

Cited by 6 publications

References 19 publications

3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds

3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds

31st Annual GP2A Medicinal Chemistry Conference

Rejuvenating the Activity of Usual Antibiotics on Resistant Gram-Negative Bacteria: Recent Issues and Perspectives

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