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. 2023 Nov 20;28(22):7678.
doi: 10.3390/molecules28227678.

Antimicrobial Properties of New Polyamines Conjugated with Oxygen-Containing Aromatic Functional Groups

Mario Inclán  1   2 , Neus Torres Hernández  1 , Alejandro Martínez Serra  1 , Gonzalo Torrijos Jabón  3 , Salvador Blasco  1 , Cecilia Andreu  4 , Marcel Lí Del Olmo  3 , Beatriz Jávega  5 , José-Enrique O'Connor  5 , Enrique García-España  1
Affiliations

Antimicrobial Properties of New Polyamines Conjugated with Oxygen-Containing Aromatic Functional Groups

Mario Inclán et al. Molecules. .

Abstract

Antibiotic resistance is now a first-order health problem, which makes the development of new families of antimicrobials imperative. These compounds should ideally be inexpensive, readily available, highly active, and non-toxic. Here, we present the results of our investigation regarding the antimicrobial activity of a series of natural and synthetic polyamines with different architectures (linear, tripodal, and macrocyclic) and their derivatives with the oxygen-containing aromatic functional groups 1,3-benzodioxol, ortho/para phenol, or 2,3-dihydrobenzofuran. The new compounds were prepared through an inexpensive process, and their activity was tested against selected strains of yeast, as well as Gram-positive and Gram-negative bacteria. In all cases, the conjugated derivatives showed antimicrobial activity higher than the unsubstituted polyamines. Several factors, such as the overall charge at physiological pH, lipophilicity, and the topology of the polyamine scaffold were relevant to their activity. The nature of the lipophilic moiety was also a determinant of human cell toxicity. The lead compounds were found to be bactericidal and fungistatic, and they were synergic with the commercial antifungals fluconazole, cycloheximide, and amphotericin B against the yeast strains tested.

Keywords: antimicrobial; bacteria; bactericidal; fungistatic; polyamine; synergy; yeast.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of the compounds studied in this work.
Scheme 1
Scheme 1
Synthetic route of compounds 1a–5a.
Figure 2
Figure 2
Analysis of the relationship between the average MIC values of the compounds considered in this work for the E. coli, S. aureus, and S. cerevisiae strains employed and their whole charge.
Figure 3
Figure 3
Analysis of the relationship between the average MIC values of the compounds considered in this work for the E. coli, S. aureus, and S. cerevisiae strains employed, and their ClogD values.
Figure 4
Figure 4
Sinergy between compounds 4a or 5a, and fluconazole or cycloheximide in the strain BY4741/YEplac195. On the left, a scheme of the plate used for these experiments is shown. In each sector, 30 μL of a ten-fold dilution of each one of the tubes prepared as described in the Materials and Methods section was applied. On the right, a representative image of the resulting growth in the plate is shown: (A) fluconazole and compound 4a; (B) cycloheximide and compound 4a; (C) fluconazole and compound 5a; (D) cycloheximide and compound 5a.
Figure 5
Figure 5
Analysis of the relationship between the average MIC and IC50 values of the compounds considered in this work, and their ClogD. Extended plots for 4a and 5a are also included to better appreciate the differences.
Figure 6
Figure 6
Structures of the conjugated polyamines 6a, 7a [44], and 8a, based on macrocyclic scaffold 5b considered in this work.
Figure 7
Figure 7
Cytotoxicity in the human Jurkat cell line was evaluated for the compounds described in this section using a propidium iodide viability assay via flow cytometry. The MIC values for each compound in the three tested strains are also shown. Data show the average of three independent experiments.
Figure 8
Figure 8
Determination of the ATP intracellular levels of cells treated with the compounds 5a and 6a for 20 h via bioluminescence. Experiments were carried out as described in the Materials and Methods section. Briefly, 50 OD600 units of yeast cultures and 1.5 OD600 units of bacterial ones were used. Experiments were carried out at least in triplicate and the presented data correspond to the normalisation of each average value to that found in untreated cells; the standard deviation was less than 5% in all cases. U—untreated cells, F—fluconazole, A—amphotericin B, D—doxycycline, and AMP—ampicillin.
Figure 9
Figure 9
Average values obtained from three independent experiments to determine the lytic activity of the polyamines studied in this work. Time-kill analyses were carried out as described in the Materials and Methods section. The values shown are relative to those found at time 0 in the untreated samples, for which a value of 100 was assigned. The standard deviation was less than 5% in all cases.
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