ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

Willmen Youngsaye,Susan Lindquist,Stuart L Schreiber,Benjamin Vincent,Michelle Palmer,Cathy L Hartland,Sivaraman Dandapani,Carrie A Mosher,Benito Munoz,Amal Ting,Partha P Nag,Barbara J Morgan,Joshua A Bittker,Luke Whitesell

doi:10.3762/bjoc.9.171

Abstract

The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure–activity relationships led to the discovery of ML212.

Highlights

Discovery of antimicrobial agents possessing unique structural motifs or a novel mechanism of action is critical to counter and control the rising incidence of drug-resistant pathogens [1,2,3,4,5,6].Chemosensitization of resistant organisms is a complementary approach that capitalizes upon the existing arsenal of antimicrobials to combat this medical dilemma [7,8,9,10]
The C. albicans clinical isolates used in this study demonstrate a range of resistance to the widely prescribed triazole antimycotic fluconazole (Flc) [12], and the objective was to identify novel small molecules capable of surmounting this inherent resistance [13,14,15,16]
The C. albicans strains used in the primary screen and secondary assay 1

Summary

Introduction

Discovery of antimicrobial agents possessing unique structural motifs or a novel mechanism of action is critical to counter and control the rising incidence of drug-resistant pathogens [1,2,3,4,5,6].Chemosensitization of resistant organisms is a complementary approach that capitalizes upon the existing arsenal of antimicrobials to combat this medical dilemma [7,8,9,10]. A total of 302,509 compounds from the MLSMR were tested at 7.5 μM for their ability to inhibit completely the growth of CaCi-2 cells that are concurrently treated with 8 μg/mL fluconazole (Figure 1). A commercial sample of compound 1 shows good activity against CaCi-2 and CaCi-8 (IC50 = 0.8 and 2.3 μM, respectively) with no apparent effect on 3T3 fibroblasts (IC50 > 26 μM).

Results

Conclusion