# Genome-Driven Discovery of Anti-MDR Bacterial Heptapeptides from a Cold-Seep-Derived Bacillus Strain

## TL;DR

Scientists discovered two new heptapeptides from a cold-seep-derived Bacillus strain that effectively inhibit multidrug-resistant bacteria.

## Contribution

The study reports the discovery of two new heptapeptides with antibacterial activity and provides insights into their stereochemistry-dependent efficacy.

## Key findings

- Two new heptapeptides, nobilamide Q3 and R3, were isolated and identified as stereoisomers of A-3302-B.
- Compound 2 and 3 inhibited the growth of MDR Staphylococcus aureus with MIC values of 3.25–6.5 μg/mL.
- Stereochemistry was found to influence antibacterial activity, offering new structure–activity relationship insights.

## Abstract

With the increasing emergence of multidrug-resistant (MDR) bacteria, there is an urgent need to discover new antibiotics. In this study, genome mining coupled with anti-bacterial assay guided the targeted isolation of two new heptapeptides nobilamide Q3 (1) and R3 (2). These compounds were identified as new stereoisomers of the known scaffold A-3302-B (3). The structures of these compounds were elucidated through a combination of MS, NMR spectroscopy and Marfey’s analysis. Anti-MDR bacterial assays showed that compounds 2 and 3 exhibited effective growth inhibition against the Gram-positive MDR bacterial strain Staphylococcus aureus CCARM 3090 with MIC values of 3.25–6.5 μg/mL. Notably, our study reveals stereochemistry-dependent differences in their antibacterial activities, providing new insights into the structure–activity relationship of this class of peptides. Finally, an analysis of the biosynthetic gene cluster responsible for their production was conducted. This study underscores the significance of exploring cold-seep environments as a reservoir for discovering new antibiotics and provides a structural starting point for the future optimization of antimicrobial peptides.