Fluconazole-Pyridoxine Bis-Triazolium Compounds with Potent Activity against Pathogenic Bacteria and Fungi Including Their Biofilm-Embedded Forms

Marsel R Garipov,Albina G Malanyeva,Alfia G Iksanova,Oksana V Bondar,Alexander M Aimaletdinov,Yurii G Shtyrlin,Alina E Sabirova,Airat R Kayumov,Elena V Nikitina,Konstantin V Balakin,Svetlana A Lisovskaya,Roman S Pavelyev

doi:10.1155/2017/4761650

Abstract

Two novel quaternary ammonium salts, bis-triazolium derivatives of fluconazole and pyridoxine, were synthesized by reaction of fluconazole with pyridoxine-based synthetic intermediates. The leading compound demonstrated pronounced antimycotic and antibacterialin vitroactivity, comparable to or exceeding that of the reference antifungal (fluconazole, terbinafine) and antibacterial/antiseptic (miramistin, benzalkonium chloride) agents. In contrast to many antimicrobials, the leading compound was also active against biofilm-embedded staphylococci andEscherichia coli. While no biofilm structure destruction occurred, all compounds were able to diffuse into the matrix and reduce the number of colony-forming units by three orders of magnitude at 16 × MBC. The leading compound was significantly less toxic than miramistin and benzalkonium chloride and more toxic than the reference antifungal drugs. The obtained results make the described chemotype a promising starting point for the development of new broad-spectrum antimicrobial therapies with powerful effect on fungal and bacterial pathogens including their biofilm-embedded forms.

Highlights

In the last decades, there is drastic increase of diseases caused by microscopic fungi
Candida albicans is one of the most widely distributed dimorphic microscopic fungi growing as both yeast and filamentous cells and causing deep and cutaneous forms of candidiasis in humans being responsible for 50–90% of all cases of candidiasis in humans [2]
Systemic fungal infections including those which are caused by C. albicans have emerged as important causes of morbidity and mortality in immunocompromised patients [3, 4]

Summary

Introduction

There is drastic increase of diseases caused by microscopic fungi. Among them, dermatomycetes, such as Trichophyton spp., which are the main causative agents for dermatomycoses in both immunocompetent and immunocompromised patients, become a serious clinical problem. The widespread distribution of microscopic fungi in the natural environment results in multiple direct contacts of humans with the pathogens. The anthropogenic factors contribute to accumulation of hazardous fungal strains in the environment and to an increased number of immunodeficient people prone to secondary mycoses caused by conditionally pathogenic fungi including Aspergillus, Rhizopus, Fusarium, Paecilomyces, Candida, and Rhodotorula [1]. Systemic fungal infections (fungemias) including those which are caused by C. albicans have emerged as important causes of morbidity and mortality in immunocompromised patients (e.g., patients with AIDS, after cancer chemotherapy, and organ or bone marrow transplantation) [3, 4]

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