Investigation of Naphthyl-Polyamine Conjugates as Antimicrobials and Antibiotic Enhancers.
Melissa M Cadelis, Liam R Edmeades, Dan Chen, Evangelene S Gill, Kyle Fraser, Florent Rouvier, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel, Brent R Copp
Author Information
Melissa M Cadelis: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. ORCID
Liam R Edmeades: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Dan Chen: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Evangelene S Gill: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Kyle Fraser: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Florent Rouvier: Membranes et Cibles Thérapeutiques (MCT), SSA, INSERM, Aix-Marseille Universite, 27 bd Jean Moulin, 13385 Marseille, France.
Marie-Lise Bourguet-Kondracki: 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.
Jean Michel Brunel: Membranes et Cibles Thérapeutiques (MCT), SSA, INSERM, Aix-Marseille Universite, 27 bd Jean Moulin, 13385 Marseille, France. ORCID
Brent R Copp: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. ORCID
As part of our search for new antimicrobials and antibiotic enhancers, a series of naphthyl- and biphenyl-substituted polyamine conjugates have been synthesized. The structurally-diverse library of compounds incorporated variation in the capping end groups and in the length of the polyamine (PA) core. Longer chain (PA-3-12-3) variants containing both 1-naphthyl and 2-naphthyl capping groups exhibited more pronounced intrinsic antimicrobial properties against methicillin-resistant (MRSA) (MIC ≤ 0.29 µM) and the fungus (MIC ≤ 0.29 µM). Closer mechanistic study of one of these analogues, , identified it as a bactericide. In contrast to previously reported diarylacyl-substituted polyamines, several examples in the current set were able to enhance the antibiotic action of doxycycline and/or erythromycin towards the Gram-negative bacteria and . Two analogues ( and ) were of note, exhibiting greater than 32-fold enhancement in activity. This latter result suggests that α,ω-disubstituted polyamines bearing 1-naphthyl- and 2-naphthyl-capping groups are worthy of further investigation and optimization as non-toxic antibiotic enhancers.
