Genome Mining-Driven Isolation of New Gromomycins and Insights into Their Mode of Action

TL;DR

Scientists discovered new gromomycin antibiotics that kill drug-resistant bacteria by damaging their cell membranes, using genome mining to find and isolate these compounds.

Contribution

The discovery of new gromomycin derivatives and their novel membrane-targeting mechanism against drug-resistant bacteria.

Findings

Gromomycins cause potassium ion leakage and membrane depolarization in bacteria, leading to cell death.

Supplementation with membrane lipids neutralizes gromomycin activity, indicating a direct membrane-targeting mechanism.

Genome mining successfully identified new bioactive gromomycin derivatives with activity against vancomycin-resistant enterococci.

Abstract

The growing threat
of multidrug-resistant bacterial infections
highlights the urgent need for antibiotics with novel mechanisms of
action. Gromomycins, a newly identified class of triterpene antibiotics,
exhibit potent activity against Gram-positive bacteria, including
drug-resistant species, through a previously uncharacterized mode
of action. Here, we report the discovery of a gromomycin-like biosynthetic
gene cluster in the Actinoplanes genus through a
genome mining approach, leading to the isolation and characterization
of new bioactive derivatives that overcome resistance to clinically
used drugs in vancomycin-resistant enterococci. Mechanistic studies
revealed that gromomycins induce rapid potassium ion leakage and depolarization
of the bacterial membrane, resulting in bactericidal activity against Staphylococcus aureus. Gromomycins disrupt the integrity
of the cytoplasmic membrane, as evidenced by large pore formation,
leakage of intracellular contents, and subsequent cell lysis. Supplementation
with membrane lipids and fatty acids neutralized their antibacterial
activity, suggesting a direct membrane-targeting mechanism, further
supported by the inability to raise gromomycin resistance and their
toxic effects on eukaryotic cells. Collectively, these findings deepen
our understanding of gromomycin activity and demonstrate the utility
of genome mining to uncover structurally novel and biologically active
natural products.

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