Researchers identify bifunctional antibiotic

Sean F. Brady and colleagues reported in Science in May 2022 that they had identified a new antibiotic, cilagicin, by mining bacterial genome data rather than isolating a compound first from a cultured microbe. The team said it used bioinformatic analysis of biosynthetic gene clusters to predict a previously unknown lipopeptide, then chemically synthesized it in the lab. (science.org) Science described the compound as a bifunctional lipopeptide antibiotic that evades resistance, and the paper linked that property to the way the molecule hits two essential targets in bacterial cell-wall construction. ### What exactly did the researchers find? (science.org) The Science paper identified cilagicin as a “naturally inspired lipopeptide antibiotic” discovered through analysis of a cryptic biosynthetic gene cluster. The authors said they screened nonribosomal peptide synthetase gene clusters from about 10,000 sequenced bacterial genomes to look for candidates with unusual mechanisms of action. Zongqiang Wang, Bimal Koirala, Yozen Hernandez, Matthew Zimmerman and Brady were listed as authors on the study. The paper said the team used phylogenetic analysis of condensation starter-domain sequences to pinpoint the cil gene cluster, then synthesized the predicted molecule rather than relying on the source organism to produce it under laboratory conditions. (science.org) ### Why is cilagicin described as bifunctional? Cilagicin was described as bifunctional because it sequesters two distinct undecaprenyl phosphate molecules used in bacterial cell-wall biosynthesis. The Science paper said those two targets are indispensable lipid carriers, and that dual binding underpins the antibiotic’s activity. (science.org) The Rockefeller University said in a 2022 news release that the compound employed a novel mechanism and showed activity against drug-resistant bacteria in mice. That release said the molecule was derived from computer models of bacterial gene products, matching the paper’s account of a computationally guided discovery process. (science.org) ### What does “low resistance potential” mean here? The Science paper did not frame the finding as a clinical outcome in people. It said instead that cilagicin showed an “absence of detectable resistance” in laboratory tests and among multidrug-resistant clinical isolates examined by the researchers. (science.org) That distinction matters because the evidence in the paper is preclinical. The reported resistance result refers to experimental testing in the lab and against bacterial isolates, not to resistance patterns observed in widespread medical use. ### How was the antibiotic found without growing the producing microbe? (rockefeller.edu) The authors said many bacterial biosynthetic gene clusters remain silent in laboratory conditions, leaving their products unidentified. Their approach was to infer the likely structure of a lipopeptide from genome sequences, then make the molecule synthetically. (science.org) Science said this strategy amounted to bioinformatic prospecting and synthesis. Rockefeller’s release said the work suggested a new generation of antibiotics could be derived from computational models, though that statement was presented as an implication of the study rather than a clinical milestone. (science.org) ### What happened after the 2022 paper? ACS Infectious Diseases later published follow-on work on cilagicin derivatives, including an optimized candidate identified from the same antibiotic family. That paper said cilagicin had strong activity against clinically relevant Gram-positive pathogens but that serum binding reduced its in vivo efficacy, prompting efforts to improve the scaffold. (science.org) A separate study in ACS Infectious Diseases also reported additional antibiotics found through related bioinformatic screening for compounds with similar resistance-evading behavior. That work named paenilagicin and virgilagicin among compounds that did not develop resistance after prolonged exposure in the reported experiments. (science.org) ### Where can readers find the primary paper? The primary report is the Science article “Bioinformatic prospecting and synthesis of a bifunctional lipopeptide antibiotic that evades resistance.” The listed authors are Zongqiang Wang, Bimal Koirala, Yozen Hernandez, Matthew Zimmerman and Sean F. Brady, and later follow-up work appeared in ACS Infectious Diseases on optimized development candidates from the cilagicin series. (pmc.ncbi.nlm.nih.gov) (science.org) (pubs.acs.org)