Holomycin, an Antibiotic Secondary Metabolite, Is Required for Biofilm Formation by the Native Producer Photobacterium galatheae S2753.

While the effects of antibiotics on microorganisms are widely studied, it remains less well understood how antibiotics affect the physiology of the native producing organisms. Here, using a marine bacterium, S2753, that produces the antibiotic holomycin, we generated a holomycin-deficient strain by in-frame deletion of , the core gene responsible for holomycin production. Mass spectrometry analysis of cell extracts confirmed that the Δ strain did not produce holomycin and that the mutant was devoid of antibacterial activity. Biofilm formation of the Δ strain was significantly reduced compared to that of wild-type S2753 and was restored in an complementary mutant. Consistent with this, exogenous holomycin, but not its dimethylated and less antibacterial derivative, S,S'-dimethyl holomycin, restored the biofilm formation of the Δ strain. Furthermore, zinc starvation was found to be essential for both holomycin production and biofilm formation of S2753, although the molecular mechanism remains elusive. Collectively, these data suggest that holomycin promotes biofilm formation of S2753 via its ene-disulfide group. Lastly, the addition of holomycin at subinhibitory concentrations also enhanced the biofilms of four other strains. likely gains an ecological advantage from producing holomycin as both an antibiotic and a biofilm stimulator, which facilitates nutrition acquisition and protects from environmental stresses. Studying the function of antibiotic compounds in the native producer will shed light on their roles in nature and could point to novel bioprospecting strategies. Despite the societal impact of antibiotics, their ecological functions remain elusive and have mostly been studied by exposing nonproducing bacteria to subinhibitory concentrations. Here, we studied the effects of the antibiotic holomycin on its native producer, S2753, a bacterium. Holomycin provides a distinct advantage to S2753 both as an antibiotic and by enhancing biofilm formation in the producer. species successfully thrive in global marine ecosystems, where they play critical ecological roles as free-living, symbiotic, or pathogenic bacteria. Genome mining has demonstrated that many have the potential to produce several bioactive compounds, including To unravel the contribution of the microbial metabolites to the development of marine microbial ecosystems, better insight into the function of these compounds in the producing organisms is needed. Our finding provides a model to pursue this and highlights the ecological importance of antibiotics to the fitness of the producing organisms.