Resistance-Guided Discovery of Elfamycin Antibiotic Producers with Antigonococcal Activity

The rise of bacterial antibiotic resistance coupled with a diminished antibiotic drug pipeline underlines the importance of developing rational strategies to discover new antimicrobials. Microbially derived natural products are the basis for most of the antibiotic arsenal available to modern medicine. Here, we demonstrate a resistance-based approach to identify producers of elfamycins, an under-explored class of natural product antibiotics that target the essential translation factor EF-Tu. Antibiotic producers carry self-resistance genes to avoid suicide. These genes are often found within the same biosynthetic gene cluster (BGC) responsible for making the antibiotic, and we exploited this trait to identify members of the kirromycin class of elfamycin producers. Genome mining of Streptomyces spp. led to the identification of three isolates that harbor kirromycin-resistant EF-Tu (EF-Tu^KirR) within predicted natural product BGCs. Activity-guided purification on extracts of one of the Streptomyces isolates, which was not known to produce an elfamycin, identified it as a producer of phenelfamycin B, a linear polyketide. Phenelfamycin B demonstrates impressive antibacterial activity (MIC ∼ 1 μg/mL) against multidrug-resistant Neisseria gonorrhoeae, a clinically important Gram negative pathogen. The antigonococcal activity of phenelfamycin was shown to be the result of inhibition of protein biosynthesis by binding to EF-Tu. These results indicate that a resistance-based approach of identifying elfamycin producers is translatable to other antibiotic classes that can identify new and overlooked antibiotics necessary to address the antibiotic crisis.