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Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism

James Peek1, Mirjana Lilic2, Daniel Montiel1

  • 1Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.

Nature Communications
|October 10, 2018
PubMed

Insights

New rifamycin-like compounds called kanglemycins combat antibiotic resistance. Discovered in soil, these kanglemycins (Kangs) effectively target resistant bacterial RNA polymerases, offering hope against drug-resistant infections.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Discovery

Background:

  • Rifamycin antibiotics (Rifs) are crucial for treating bacterial infections like tuberculosis by inhibiting bacterial RNA polymerases (RNAPs).
  • Increasing antibiotic resistance (RifR) to Rifs threatens their clinical utility, necessitating the search for novel therapeutic agents.
  • Resistance mechanisms observed clinically may also exist in natural environments, suggesting potential for discovering resistance-circumventing compounds.

Purpose of the Study:

  • To investigate whether bacteria in natural environments produce rifamycin congeners active against clinically relevant rifamycin-resistant phenotypes.
  • To identify and characterize novel rifamycin derivatives from soil metagenomes with potential to overcome existing resistance mechanisms.

Main Methods:

  • Surveyed soil metagenomes to identify gene clusters involved in the biosynthesis of novel rifamycin congeners.
  • Utilized structural and mechanistic analyses to elucidate the mode of action of identified compounds against resistant bacterial RNA polymerases.
  • Performed in vitro and in vivo assays to evaluate the activity of kanglemycins against common clinically relevant RifR mutations.

Main Results:

  • Identified a family of gene clusters encoding the biosynthesis of kanglemycins (Kangs), novel rifamycin congeners.
  • Kangs demonstrated potent in vitro and in vivo activity against bacterial RNA polymerases harboring common clinically relevant RifR mutations.
  • Mechanistic studies revealed that Kangs inhibit resistant RNAP by interfering with 5'-initiating substrate binding, a different mechanism than Rifs.

Conclusions:

  • Soil microbiomes are a promising source for discovering novel antibiotic analogues capable of circumventing established resistance mechanisms.
  • Kanglemycins represent a new class of compounds with potential therapeutic applications against rifamycin-resistant bacterial infections.
  • Understanding the unique inhibitory mechanism of Kangs provides insights for designing next-generation antibiotics to combat resistance.

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