Structural design of microbicidal cationic oligomers and their synergistic interaction with azoles against Candida albicans

Yuan Yuan,Feng Zhou,Yugen Zhang,Haibin Su

doi:10.1038/s41598-019-48322-x

Abstract

Membrane-disrupting synthetic antimicrobial polymers have been well developed as antimicrobial peptide (AMP) mimics to mitigate antimicrobial resistance (AMR). However, synthetic polymers possess inherent drawbacks, being a mixture of different chain lengths, which restricts their clinical applications. In fact, synthetic oligomers with defined chain length and molecular structure could be better representatives of AMPs. Herein, a series of novel imidazolium-ammonium oligomers developed in this work exhibit excellent broad spectrum antimicrobial activity, specifically the salient structure dependent high efficiency against C. albicans. Moreover, synergistic effect emerged when the combined azoles and synthetic oligomers were applied against C. albicans. The detail structural coupling between azoles and oligomers was scrutinized through molecular dynamics simulations to unravel the interaction details with the atomistic resolution. The labile interaction between oligomer and azoles facilitated the transfer of drug into fungal cells, which can be a synergistic solution to prevent the development of resistance on C. albicans.

Highlights

Antimicrobial resistance (AMR) is one of the major global healthcare threats[1,2]
Combinations of azoles and synthetic oligomers were tested on C. albicans and the structure dependent synergistic effects were established and further investigated with molecular dynamics simulations
Imidazole and DABCO are selected as synthons to construct oligomers with suitable linkers and ending groups to achieve optimum antimicrobial property by tuning their charge density, hydrophobicity and structure flexibility (Fig. 1)

Summary

Introduction

Antimicrobial resistance (AMR) is one of the major global healthcare threats[1,2]. Its development is closely related to the overuse of antibiotics, including clinical and non-therapeutic applications[3]. Combinations of azoles and synthetic oligomers were tested on C. albicans and the structure dependent synergistic effects were established and further investigated with molecular dynamics simulations. IDPBX8, with a more flexible butene linker, was the most effective antifungal compound with MIC of 8–31 μg mL−1 against C. albicans.

Results

Conclusion