Quorum-sensing gene regulates hormetic effects induced by sulfonamides in Comamonadaceae

Hormesis is a toxicological phenomenon whereby exposure to low-dose stress results in the stimulation of various biological endpoints. Among these, the induction of cell proliferation by antibiotics is critical, but the underlying molecular mechanisms remain poorly understood. Here, we showed that sulfonyl-containing chemicals (e.g., sulfonamides) can induce cell proliferation hormesis in Comamonas testosteroni. An investigation of the hormesis mechanism revealed that low-dose sulfonamides potentially interact with the LuxR-type quorum-sensing protein LuxR solo, thereby triggering the transcription of 3-ketoacyl-CoA thiolase, a key enzyme of fatty acid beta-oxidation. This provides additional ATP, NADPH, and acetyl-CoA for macromolecule biosynthesis, allowing cells to synthesize sufficient nucleotides to support rapid cell growth. Our work reports on a previously unknown mechanism for the hormetic effect and highlights its generality in the Comamonadaceae family. IMPORTANCE Antibiotics can induce dose-dependent hormetic effects on bacterial cell proliferation, i.e., low-dose stimulation and high-dose inhibition. However, the underlying molecular basis has yet to be clarified. Here, we showed that sulfonamides play dual roles as a weapon and signal against Comamonas testosteroni that can modulate cell physiology and phenotype. Subsequently, through investigating the hormesis mechanism, we proposed a comprehensive regulatory pathway for the hormetic effects of Comamonas testosteroni low-level sulfonamides and determined the generality of the observed regulatory model in the Comamonadaceae family. Considering the prevalence of Comamonadaceae in human guts and environmental ecosystems, we provide critical insights into the health and ecological effects of antibiotics.