Research Article: Chemogenomic profiling in yeast reveals antifungal mode-of-action of polyene macrolactam auroramycin

Date Published: June 10, 2019

Publisher: Public Library of Science

Author(s): Jin Huei Wong, Mohammad Alfatah, Kiat Whye Kong, Shawn Hoon, Wan Lin Yeo, Kuan Chieh Ching, Corinna Jie Hui Goh, Mingzi M. Zhang, Yee Hwee Lim, Fong Tian Wong, Prakash Arumugam, Yoshikazu Ohya.

http://doi.org/10.1371/journal.pone.0218189

Abstract

In this study, we report antifungal activity of auroramycin against Candida albicans, Candida tropicalis, and Cryptococcus neoformans. Auroramycin, a potent antimicrobial doubly glycosylated 24-membered polyene macrolactam, was previously isolated and characterized, following CRISPR-Cas9 mediated activation of a silent polyketide synthase biosynthetic gene cluster in Streptomyces rosesporous NRRL 15998. Chemogenomic profiling of auroramycin in yeast has linked its antifungal bioactivity to vacuolar transport and membrane organization. This was verified by disruption of vacuolar structure and membrane integrity of yeast cells with auroramycin treatment. Addition of salt but not sorbitol to the medium rescued the growth of auroramycin-treated yeast cells suggesting that auroramycin causes ionic stress. Furthermore, auroramycin caused hyperpolarization of the yeast plasma membrane and displayed a synergistic interaction with cationic hygromycin. Our data strongly suggest that auroramycin inhibits yeast cells by causing leakage of cations from the cytoplasm. Thus, auroramycin’s mode-of-action is distinct from known antifungal polyenes, reinforcing the importance of natural products in the discovery of new anti-infectives.

Partial Text

Natural products (NPs) are a prolific source of bioactive leads with approximately 80% of clinical anti-infectives, including antifungal agents, derived from natural products [1]. Although fungal infections are on the rise, especially in expanding immuno-compromised populations [2] caused by AIDS and intensive chemotherapy cancer treatments, the number of available polyene and azole antifungal agents have largely remained the same from 1950s-1970s. A polyene macrolactone, amphotericin B is one of the leading drugs to combat serious infections due to its high potency, broad range and low frequency of resistant pathogens. Several known antifungal agents such as nystatin, filipin, and pimaricin also belong to the polyene macrolactone family. Due to growing resistance to azoles, amphotericin B is often the last line of defence for life-threatening fungal infections but its use is limited by its cytotoxicity. It is therefore a matter of paramount importance to discover antifungal agents, preferably with new modes-of-actions.

 

Source:

http://doi.org/10.1371/journal.pone.0218189