Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Abstract

The bacteria harbored by fungus-growing ants produce a variety of small molecules that help maintain a complex multilateral symbiosis. In a survey of antifungal compounds from these bacteria, we discovered selvamicin, an unusual antifungal polyene macrolide, in bacterial isolates from two neighboring ant nests. Selvamicin resembles the clinically important antifungals nystatin A₁ and amphotericin B, but it has several distinctive structural features: a noncationic 6-deoxymannose sugar at the canonical glycosylation site and a second sugar, an unusual 4-O-methyldigitoxose, at the opposite end of selvamicin's shortened polyene macrolide. It also lacks some of the pharmacokinetic liabilities of the clinical agents and appears to have a different target. Whole genome sequencing revealed the putative type I polyketide gene cluster responsible for selvamicin's biosynthesis including a subcluster of genes consistent with selvamicin's 4-O-methyldigitoxose sugar. Although the selvamicin biosynthetic cluster is virtually identical in both bacterial producers, in one it is on the chromosome, in the other it is on a plasmid. These alternative genomic contexts illustrate the biosynthetic gene cluster mobility that underlies the diversity and distribution of chemical defenses by the specialized bacteria in this multilateral symbiosis.

Keywords: antifungal; biosynthesis; horizontal gene transfer; natural products; symbiosis.

Fig. 1.

Structures of selvamicin and antifungal polyene natural products currently in clinical use.

Fig. 2.

Key NMR correlations establishing the planar structure of selvamicin.

Fig. 3.

Growth inhibition of C. albicans, S. cerevisiae, T. harzianum, and A. fumigatus by selvamicin.

Fig. 4.

(A) Genomes of Pseudonocardia isolates LS1 and LS2. The selvamicin BGC in each is marked with a red box. (B) Selvamicin BGCs from LS1 and LS2. Mobile genetic element genes flanking the selvamicin clusters are shown as red arrows.

Fig. 5.

Nystatin and selvamicin BGCs. Polyketide synthase genes are labeled with bold font. Coloring of the polyketide-derived portions of the nystatin A₁ and selvamicin structures corresponds to the genes encoding their biosynthesis.