Researchers report bifunctional antibiotic

Sean F. Brady and colleagues at Rockefeller University reported in *Science* in May 2022 that they had discovered and synthesized a new antibiotic, cilagicin, by mining bacterial genome data for hidden drug candidates. The paper described cilagicin as a bifunctional lipopeptide antibiotic derived from a biosynthetic gene cluster identified through bioinformatic analysis of about 10,000 sequenced bacterial genomes. (europepmc.org) The work was published online on May 26, 2022, and in the May 27, 2022 print issue of *Science*. (science.org) ### Why is this being described as a “bifunctional” antibiotic? (europepmc.org) The *Science* paper said cilagicin is bifunctional because it sequesters two distinct undecaprenyl phosphate molecules that bacteria need for cell-wall biosynthesis. Those two lipid carriers are both indispensable to the process, and the authors said binding both at once could make resistance harder to evolve than with drugs aimed at only one target. The molecule was “naturally inspired” rather than directly isolated from a cultured microbe. Zongqiang Wang, Bimal Koirala, Yozen Hernandez, Matthew Zimmerman and Brady wrote that they chemically synthesized cilagicin after reconstructing its likely structure from the cil biosynthetic gene cluster. (science.org) ### How did the researchers find it without starting from a cultured bacterium? The study said the team searched nonribosomal peptide synthetase gene clusters from roughly 10,000 bacterial genomes and focused on cryptic lipopeptide pathways that had not yielded known natural products. (science.org) The researchers used phylogenetic analysis of condensation starter-domain sequences to flag the cil gene cluster as a candidate source of an uncharacterized antibiotic. Rockefeller University said the approach relied on computer models of bacterial gene products rather than conventional cultivation-first screening. (science.org) Brady said in the university release that the result validated a different route to antibiotic discovery, one based on predicting molecules from genomic blueprints and then making them synthetically. ### What did the paper say cilagicin did in tests? The abstract reported antimicrobial activity against multiple Gram-positive pathogens and said the compound showed an absence of detectable resistance in laboratory tests and among multidrug-resistant clinical isolates. (science.org) Rockefeller University said the antibiotic was active against methicillin-resistant *Staphylococcus aureus*, *Clostridioides difficile* and other pathogens, and that it worked in mice after chemical optimization for animal use. EurekAlert’s summary of the paper said cilagicin showed broad activity against several difficult-to-treat Gram-positive bacteria in laboratory assays. (rockefeller.edu) That matches the paper’s central claim that the compound’s dual binding mechanism could help it evade common resistance pathways. ### What is the main limitation readers should keep in mind? The paper reported preclinical findings, not a marketed medicine. The results described laboratory tests, multidrug-resistant clinical isolates and mouse experiments, but the sources reviewed here do not show any human clinical trial data for cilagicin. (europepmc.org) A related *Science* commentary, “Antibiotics made to order,” framed the study as an example of using bioinformatics to identify biosynthetic gene clusters and then synthesize predicted compounds. That places cilagicin in the discovery stage rather than the regulatory stage. (eurekalert.org) ### Where does the story stand now? The original report dates to May 26-27, 2022, even though a *Science Magazine* social post resurfaced it later. The primary paper is “Bioinformatic prospecting and synthesis of a bifunctional lipopeptide antibiotic that evades resistance,” published in *Science* 376(6596):991-996, by Wang, Koirala, Hernandez, Zimmerman and Brady. (europepmc.org) Readers looking for the next step should watch for later preclinical or clinical follow-up work from Brady’s group or other teams building on cilagicin and related dual-target antibiotics. (science.org)