MKM: a natural antibiotic locking the bacterial ribosome at the E-site

Manikomycin (MKM), a newly identified cyclic depsipeptide from Streptomyces rimosus, binds the E-site of the bacterial 50S ribosome to block translocation and halt protein synthesis. It kills multidrug‑resistant Enterobacteriaceae and mycobacteria, with resistance arising from mutations in 23S rRNA near the E-site or loss of ribosomal protein L35; the producer carries ManE, a methyltransferase that methylates Cm2395 to confer self-resistance. Cryo-EM reveals MKM in the primary E-site pocket formed by 23S rRNA and L35; biochemical and ribosome profiling data show context‑dependent translation inhibition. Activity is limited in many bacteria due to uptake, but MKM offers a new scaffold for antibiotic development, supported by in vitro, ex vivo, and pharmacokinetic data.