2. Academic Validation
  3. Valorisation of the diterpene podocarpic acid - Antibiotic and antibiotic enhancing activities of polyamine conjugates

Valorisation of the diterpene podocarpic acid - Antibiotic and antibiotic enhancing activities of polyamine conjugates

  • Bioorg Med Chem. 2022 Jun 15;64:116762. doi: 10.1016/j.bmc.2022.116762.
Steven A Li 1,  Melissa M Cadelis 1,  Rebecca C Deed 2,  Hana Douafer 3,  Marie-Lise Bourguet-Kondracki 4,  Jean Michel Brunel 3,  Brent R Copp 5
Affiliations

Affiliations

  • 1 School of Chemical Sciences, The University of Auckland, Waipapa Taumata Rau, Private Bag 92019, Auckland 1142, New Zealand.
  • 2 School of Chemical Sciences, The University of Auckland, Waipapa Taumata Rau, Private Bag 92019, Auckland 1142, New Zealand; School of Biological Sciences, The University of Auckland, Waipapa Taumata Rau, Private Bag 92019, Auckland 1142, New Zealand.
  • 3 Aix-Marseille Universite, INSERM, SSA, MCT, Faculté de Pharmacie, 27 bd Jean Moulin, 13385 Marseille, France.
  • 4 Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 57 rue Cuvier (C.P. 54), 75005 Paris, France.
  • 5 School of Chemical Sciences, The University of Auckland, Waipapa Taumata Rau, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.copp@auckland.ac.nz.
PMID: 35477062 DOI: 10.1016/j.bmc.2022.116762
Abstract

As part of our search for new antimicrobials and Antibiotic adjuvants, a series of podocarpic acid-polyamine conjugates have been synthesized. The library of compounds made use of the phenolic and carboxylic acid moieties of the diterpene allowing attachment of polyamines (PA) of different lengths to afford a structurally-diverse set of analogues. Evaluation of the conjugates for intrinsic antimicrobial properties identified two derivatives of interest: a PA3-4-3 (spermine) amide-bonded variant 7a that was a non-cytotoxic, non-hemolytic potent growth inhibitor of Gram-positive Staphylococcus aureus (MRSA) and 9d, a PA3-8-3 carbamate derivative that was a non-toxic selective Antifungal towards Cryptococcus neoformans. Of the compound set, only one example exhibited activity towards Gram-negative bacteria. However, in the presence of sub-therapeutic amounts of either doxycycline (4.5 µM) or erythromycin (2.7 μM) several analogues were observed to exhibit weak to modest Antibiotic adjuvant properties against Pseudomonas aeruginosa and/or Escherichia coli. The observation of strong cytotoxicity and/or hemolytic properties for subsets of the library, in particular those analogues bearing methyl ester or n-pentylamide functionality, highlighted the fine balance of structural requirements and lipophilicity for antimicrobial activity as opposed to mammalian cell toxicity.

Keywords

Antibiotic adjuvant; Antimicrobial activities; Diterpene polyamine conjugates; Podocarpic acid.

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