Genome-guided discovery of tropansamycins: antimicrobial pentaketide ansamycins

Abstract

Although ansamycins are clinically important macrolactams, their pentaketide subset exhibits limited biological activities. Genome mining of rhizosphere-derived Streptomyces sp. LR53 uncovered a cryptic pentaketide ansamycin gene cluster (tpm). Activation via 3-amino-5-hydroxybenzoic acid (AHBA) feeding, promoter replacement, and deletion of the cytochrome P450 (CYP450) gene tpm16 enabled the discovery of seven novel metabolites, tropansamycins A–G (1– 7), establishing the seventh distinct pentaketide ansamycin scaffold. Notably, congeners 5 and 6, predominantly accumulated in the Δtpm16 mutant, exhibited potent activity against gram-negative pathogenic bacterium Xanthomonas oryzae and gram-positive bacterium Staphylococcus aureus, with MICs ranging from 2 to 8 μg/mL and were toxic to the producer strain cultivated on LB agar medium. This reveals that the CYP450 enzyme Tpm16 functions as a modification enzyme modulating the bioactivity profile of pathway intermediates. These findings not only expand the structural diversity of ansamycins but also highlight the potential of these pathogen-active ansamycins as promising leads.

Keywords

Ansamycin / Streptomyces / Genome mining / Antibacterial activity

Data availability statement

The biosynthetic gene cluster of tpm has been deposited into GenBank database under Accession No. PV541294. Crystallographic data of tropansamycin E (5) has been deposited with the Cambridge Crystallographic Data Centre (CCDC) under deposition number CCDC 2414079. All relevant data supporting the findings of this study are provided within the manuscript and the Supplementary Materials.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Haotian Wang: Writing – original draft, Investigation, Data curation. Run Jiao: Data curation. Liran Ma: Investigation. Yaoyao Li: Writing – review & editing, Data curation. Yuemao Shen: Writing – review & editing, Supervision, Project administration. Haoxin Wang: Writing – review & editing, Supervision, Project administration, Funding acquisition.

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