Amphipathic Barbiturates as Mimics of Antimicrobial Peptides and the Marine Natural Products Eusynstyelamides with Activity against Multi-resistant Clinical Isolates
We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N′-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two catio...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-08, Vol.64 (15), p.11395-11417 |
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| creator | Paulsen, Marianne H Engqvist, Magnus Ausbacher, Dominik Anderssen, Trude Langer, Manuel K Haug, Tor Morello, Glenn R Liikanen, Laura E Blencke, Hans-Matti Isaksson, Johan Juskewitz, Eric Bayer, Annette Strøm, Morten B |
| description | We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N′-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2–8 μg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase–carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria. |
| doi_str_mv | 10.1021/acs.jmedchem.1c00734 |
| format | Article |
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These N,N′-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2–8 μg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase–carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c00734</identifier><language>eng</language><publisher>American Chemical Society</publisher><subject>Basale medisinske, odontologiske og veterinærmedisinske fag: 710 ; Basic medical, dental and veterinary science disciplines: 710 ; Farmakologi: 728 ; Medical disciplines: 700 ; Medisinske Fag: 700 ; Pharmacology: 728 ; VDP</subject><ispartof>Journal of medicinal chemistry, 2021-08, Vol.64 (15), p.11395-11417</ispartof><rights>2021 The Authors. 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Med. Chem</addtitle><date>2021-08-12</date><risdate>2021</risdate><volume>64</volume><issue>15</issue><spage>11395</spage><epage>11417</epage><pages>11395-11417</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N′-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2–8 μg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase–carbapenemase production. 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| source | ACS Publications; NORA - Norwegian Open Research Archives |
| subjects | Basale medisinske, odontologiske og veterinærmedisinske fag: 710 Basic medical, dental and veterinary science disciplines: 710 Farmakologi: 728 Medical disciplines: 700 Medisinske Fag: 700 Pharmacology: 728 VDP |
| title | Amphipathic Barbiturates as Mimics of Antimicrobial Peptides and the Marine Natural Products Eusynstyelamides with Activity against Multi-resistant Clinical Isolates |
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