Promising antifungal activity of new oxadiazole against Candida krusei.

Daniella Renata Faria,Maria Sueli Soares Felipe,Franciele Abigail Vilugron Rodrigues-Vendramini,Terezinha Inez Estivalet Svidzinski,Glaucia Sayuri Arita,Admilton Gonçalves De Oliveira Junior,Patrícia De Souza Bonfim De Mendonça,Isis Regina Grenier Capoci,Karina Mayumi Sakita,Erika Seki Kioshima,Joy Sturtevant

doi:10.1371/journal.pone.0227876

Abstract

Candida krusei is one of the most common agents of invasive candidiasis and candidemia worldwide, leading to high morbidity and mortality rates. This species has become a problem due to its intrinsic resistance and reduced susceptibility to azoles and polyenes. Moreover, the number of antifungal drugs available for candidiasis treatment is limited, demonstrating the urgent need for the discovery of novel alternative therapies. In this work, the in vivo and in vitro activities of a new oxadiazole (LMM11) were evaluated against C. krusei. The minimum inhibitory concentration ranged from 32 to 64 μg/mL with a significant reduction in the colony forming unit (CFU) count (~3 log10). LMM11 showed fungicidal effect, similar to amphotericin, reducing the viable cell number (>99.9%) in the time-kill curve. Yeast cells presented morphological alterations and inactive metabolism when treated with LMM11. This compound was also effective in decreasing C. krusei replication inside and outside macrophages. A synergistic effect between fluconazole and LMM11 was observed. In vivo treatment with the new oxadiazole led to a significant reduction in CFU (0.85 log10). Furthermore, histopathological analysis of the treated group exhibited a reduction in the inflammatory area. Taken together, these results indicate that LMM11 is a promising candidate for the development of a new antifungal agent for the treatment of infections caused by resistant Candida species such as C. krusei.

Highlights

Fungal infections have emerged worldwide, accounting for about 6% of all healthcare-associated infections (HAIs), especially in the increasing population of immunocompromised patients [1,2,3,4,5]
C. krusei is assumed to be intrinsically resistant to FLC and these minimal inhibitory concentration (MIC) should not be interpreted using the cut-off levels for susceptible, dosedependent susceptible and resistant strains
LMM11 showed a synergistic effect when combined with fluconazole for both the standard strain and one clinical isolate, with fractional inhibitory concentration (FIC) values of 0.75 (Table 2)

Summary

Introduction

Fungal infections have emerged worldwide, accounting for about 6% of all healthcare-associated infections (HAIs), especially in the increasing population of immunocompromised patients [1,2,3,4,5]. Invasive candidiasis and candidemia represent a serious public health problem associated with high mortality rates, ranging from 40 to 85%, prolonged length of hospital stay and high costs [6,7,8,9]. Candida albicans was the most frequent agent isolated from clinical specimens. The epidemiology has changed with an increase in infection.

Methods

Results

Conclusion