Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators
Small molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal s...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/3/261 |
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| author | Kenneth Sue Melissa M. Cadelis Florent Rouvier Marie-Lise Bourguet-Kondracki Jean Michel Brunel Brent R. Copp |
| author_facet | Kenneth Sue Melissa M. Cadelis Florent Rouvier Marie-Lise Bourguet-Kondracki Jean Michel Brunel Brent R. Copp |
| author_sort | Kenneth Sue |
| collection | DOAJ |
| description | Small molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal species, and the ability to enhance the action of doxycycline toward the Gram-negative bacteria <i>Pseudomonas aeruginosa</i>; however, these desirable activities were commonly associated with unfavorable cytotoxicity and/or red blood cell hemolytic properties. In this paper, we report the synthesis and biological investigation of a new class of α,ω-di(indole-3-carboxamido)polyamine derivatives, leading to the identification of several analogues that exhibit antimicrobial- and antibiotic-potentiating activities without detectable cytotoxic or hemolytic properties. 5-Bromo-substituted indole analogues <b>3</b> and <b>12</b>–<b>18</b> were generally more broad-spectrum in their activity than others in the set, with <b>13b</b> (polyamine PA-3-6-3) being particularly notable for its anti-<i>Staphylococcus aureus</i>, <i>Acinetobacter baumannii</i>, and <i>Cryptococcus neoformans</i> activities (MIC ≤ 0.28 µM). The same analogue also restored the action of doxycycline toward <i>P. aeruginosa</i> with a 21-fold enhancement, while the corresponding 5-bromo-indole-3-carboxamide-PA3-7-3 analogue was able to enhance the action of both doxycycline and erythromycin toward <i>P. aeruginosa</i> and <i>Escherichia coli</i>, respectively. The analogue <b>13b</b> was capable of disrupting the bacterial membrane of both <i>S. aureus</i> and methicillin-resistant <i>S. aureus</i> (MRSA) and the outer membrane of <i>P. aeruginosa</i>, suggesting that membrane perturbation could be a mechanism of action of both intrinsic antimicrobial activities and antibiotic potentiation. |
| first_indexed | 2024-04-24T18:30:28Z |
| format | Article |
| id | doaj.art-ba3fb6e312db492eb6fe4ad0f6943c06 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-04-24T18:30:28Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-ba3fb6e312db492eb6fe4ad0f6943c062024-03-27T13:27:48ZengMDPI AGBiomolecules2218-273X2024-02-0114326110.3390/biom14030261Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic PotentiatorsKenneth Sue0Melissa M. Cadelis1Florent Rouvier2Marie-Lise Bourguet-Kondracki3Jean Michel Brunel4Brent R. Copp5School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandSchool of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandMembranes et Cibles Thérapeutiques, SSA, INSERM, Aix-Marseille Universite, 27 Bd Jean Moulin, 13385 Marseille, FranceLaboratoire Molécules de Communication et Adaptation des Micro-Organismes, UMR 7245 CNRS, Muséum National d’Histoire Naturelle, 57 Rue Cuvier (C.P. 54), 75005 Paris, FranceMembranes et Cibles Thérapeutiques, SSA, INSERM, Aix-Marseille Universite, 27 Bd Jean Moulin, 13385 Marseille, FranceSchool of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New ZealandSmall molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal species, and the ability to enhance the action of doxycycline toward the Gram-negative bacteria <i>Pseudomonas aeruginosa</i>; however, these desirable activities were commonly associated with unfavorable cytotoxicity and/or red blood cell hemolytic properties. In this paper, we report the synthesis and biological investigation of a new class of α,ω-di(indole-3-carboxamido)polyamine derivatives, leading to the identification of several analogues that exhibit antimicrobial- and antibiotic-potentiating activities without detectable cytotoxic or hemolytic properties. 5-Bromo-substituted indole analogues <b>3</b> and <b>12</b>–<b>18</b> were generally more broad-spectrum in their activity than others in the set, with <b>13b</b> (polyamine PA-3-6-3) being particularly notable for its anti-<i>Staphylococcus aureus</i>, <i>Acinetobacter baumannii</i>, and <i>Cryptococcus neoformans</i> activities (MIC ≤ 0.28 µM). The same analogue also restored the action of doxycycline toward <i>P. aeruginosa</i> with a 21-fold enhancement, while the corresponding 5-bromo-indole-3-carboxamide-PA3-7-3 analogue was able to enhance the action of both doxycycline and erythromycin toward <i>P. aeruginosa</i> and <i>Escherichia coli</i>, respectively. The analogue <b>13b</b> was capable of disrupting the bacterial membrane of both <i>S. aureus</i> and methicillin-resistant <i>S. aureus</i> (MRSA) and the outer membrane of <i>P. aeruginosa</i>, suggesting that membrane perturbation could be a mechanism of action of both intrinsic antimicrobial activities and antibiotic potentiation.https://www.mdpi.com/2218-273X/14/3/261indolepotentiatorantimicrobialpolyamineantibioticsantifungal agents |
| spellingShingle | Kenneth Sue Melissa M. Cadelis Florent Rouvier Marie-Lise Bourguet-Kondracki Jean Michel Brunel Brent R. Copp Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators Biomolecules indole potentiator antimicrobial polyamine antibiotics antifungal agents |
| title | Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators |
| title_full | Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators |
| title_fullStr | Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators |
| title_full_unstemmed | Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators |
| title_short | Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators |
| title_sort | antimicrobial indole 3 carboxamido polyamine conjugates target bacterial membranes and are antibiotic potentiators |
| topic | indole potentiator antimicrobial polyamine antibiotics antifungal agents |
| url | https://www.mdpi.com/2218-273X/14/3/261 |
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