Mechanism of action of and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571

Antimicrob Agents Chemother. 2012 Aug;56(8):4463-5. doi: 10.1128/AAC.06354-11. Epub 2012 May 29.


LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10(-11) to 1.2 × 10(-9). Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites / genetics
  • Clostridioides difficile / drug effects*
  • Clostridioides difficile / genetics*
  • Drug Resistance, Bacterial / genetics
  • Enterocolitis, Pseudomembranous / drug therapy
  • Enterocolitis, Pseudomembranous / microbiology
  • Humans
  • Microbial Sensitivity Tests
  • Peptide Chain Elongation, Translational / drug effects*
  • Peptide Elongation Factor Tu / genetics*
  • Protein Structure, Tertiary
  • Thiazoles / pharmacology*


  • Anti-Bacterial Agents
  • LFF571
  • Thiazoles
  • Peptide Elongation Factor Tu