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Genome-Mining Based Discovery of Pyrrolomycin K and L from the Termite-Associated Micromonospora sp. RB23

Summary

Researchers discovered two new antimicrobial compounds called pyrrolomycins from a bacterium found in termite guts using genome analysis and advanced chemistry techniques. These compounds are modified versions of known antimicrobial molecules, featuring halogenated structures. Interestingly, the bacteria appears to protect itself from its own toxic compounds through chemical modifications, a strategy that researchers believe could inform the design of new antibiotics to combat drug-resistant bacteria.

Background

Natural products from symbiotic microbes represent a rich source of structurally diverse and bioactive molecules. Actinomycetota, particularly those involved in protective symbiosis with insects, are prolific producers of natural products. Micromonospora species are well-recognized for producing structurally diverse and biologically active natural products with antimicrobial properties.

Objective

This study investigated the termite-associated Micromonospora sp. RB23 to elucidate the basis of its antimicrobial activity through de novo genome sequencing and biosynthetic gene cluster analysis. The research aimed to identify and characterize novel pyrrolomycin-like compounds predicted by a type I polyketide synthase biosynthetic gene cluster containing five halogenase genes.

Results

Genome mining uncovered a type I polyketide synthase biosynthetic gene cluster encoding five halogenases. Fermentation and metabolomic analysis led to isolation of two pyrrolomycin derivatives: N-methylated pyrrolomycin K and N-acetyl-cysteinylated pyrrolomycin L. The N-acetyl-cysteine adduct showed weak activity against S. aureus and E. coli, while N-methylation abolished antimicrobial activity, suggesting these modifications function as detoxification mechanisms.

Conclusion

The study demonstrates that genome-mining-guided discovery successfully identified novel pyrrolomycin derivatives with structural modifications not previously reported. N-methylation and mycothiol-based conjugation appear to be self-tolerance mechanisms enhancing producer resistance. These findings broaden the chemical diversity of pyrrolomycins and illustrate novel detoxification strategies employed by the producing Micromonospora isolate.
  • Published in:Journal of Natural Products,
  • Study Type:Experimental Research,
  • Source: 10.1021/acs.jnatprod.5c01051; PMID: 41195882
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