| Summary: | Actinomycetes are recognized for producing diverse bioactive natural products, yet most biosynthetic gene clusters (BGCs) remain inactive under laboratory conditions. Rare actinomycetes from extreme environments represent underexplored reservoirs of metabolic potential. This study investigates <i>Actinomadura</i> sp. TRM71106, a rare actinomycete isolated from the Taklamakan Desert, through integrated genomic and metabolomic approaches. Genome sequencing revealed 45 secondary metabolic BGCs, including BGC38 showing 65% nucleotide similarity to the rifamycin BGC. Gene cluster networking and linear comparisons predicted its capacity to encode novel rifamycin analogs. Targeted activation strategies—overexpression of the pathway-specific regulator <i>LuxR</i> combined with metabolite isolation—mark the first activation of a rifamycin-like BGC in desert actinomycetes. This study highlights the untapped biosynthetic potential of rare actinomycetes in extreme environments and establishes <i>Actinomadura</i> sp. TRM71106 as a novel source for rifamycin production. These results provide a promising avenue for expanding the clinical pipeline of rifamycin-derived antibiotics.
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