PT  - JOURNAL ARTICLE
AU  - Romain Brunel
AU  - Ghislaine Descours
AU  - Patricia Doublet
AU  - Sophie Jarraud
AU  - Xavier Charpentier
TI  - KKL-35 exhibits potent antibiotic activity against <em>Legionella</em> species independently of trans-translation inhibition
AID  - 10.1101/135798
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 135798
4099  - http://biorxiv.org/content/early/2017/05/15/135798.short
4100  - http://biorxiv.org/content/early/2017/05/15/135798.full
AB  - Trans-translation is a ribosome rescue system that is ubiquitous in bacteria. A new family of oxadiazole compounds that inhibit trans-translation have been found to have broad-spectrum antibiotic activity. We sought to determine the activity of KKL-35, a potent member of the oxadiazole family, against the human pathogen Legionella pneumophila and other related species that can also cause Legionnaire’s disease (LD). Consistent with the essential nature of trans-translation in L. pneumophila, KKL-35 inhibits growth of all tested L. pneumophila trains at sub-micromolar concentrations, and is active against other LD-causing Legionella species. KKL-35 is also active against L. pneumophila mutants that have evolved resistance to macrolides. KKL-35 exhibits bactericidal activity at the minimal inhibitory concentration (MIC) on all tested strains. KKL-35 inhibits multiplication of L. pneumophila in human macrophages at several stages of infection. No resistant mutants could be obtained, even during extended and chronic exposure, suggesting that resistance is not easily acquirable. Surprisingly, KKL-35 is not synergistic with other ribosome-targeting antibiotics, and remains active against L. pneumophila mutants lacking tmRNA, the essential component of trans-translation. These results indicate that the antibiotic activity of KKL-35 is not related to the specific inhibition of transtranslation and its mode of action remains to be identified. In conclusion, KKL-35 displays strong antibiotic activity against the human pathogen L. pneumophila, including in an intracellular infection model and with no detectable resistance.