Mechanism of action of and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571.
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.
Novartis Institutes for Biomedical Research, Infectious Disease Area, Emeryville, California, USA. jennifer.leeds@novartis.com
J A
JA
Leeds
M
M
Sachdeva
S
S
Mullin
J
J
Dzink-Fox
M J
MJ
Lamarche
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D016360:Clostridioides difficile / Q000187:drug effects* / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects*; D010444:Peptide Elongation Factor Tu / Q000235:genetics*; D017434:Protein Structure, Tertiary; D013844:Thiazoles / Q000494:pharmacology*; D010456:Peptides, Cyclic
D000900:Anti-Bacterial Agents; D010444:Peptide Elongation Factor Tu; D013844:Thiazoles; C573298:LFF571; D010456:Peptides, Cyclic