Costa-Martini Jonas H, Adams Eva E, Johnston Chad W
Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States.
Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, Texas 77030, United States.
J Am Chem Soc. 2025 Jun 25;147(25):21400-21407. doi: 10.1021/jacs.4c17876. Epub 2025 Jun 10.
Antibiotics are essential for modern medicine, but their use drives the evolution of antimicrobial resistance (AMR) that limits the long-term efficacy of any one drug. To keep pace with AMR and preserve our ability to treat bacterial infections, it is essential that we identify antibiotics with new structures and targets that are not affected by clinical resistance. Historically, most developmental candidates for antibiotics have come from microbial natural products, as they feature chemical structures and biological activities that have been honed over millions of years of evolution. Unfortunately, as classical bioactivity screens for natural product discovery are blind to the pharmacological properties of their hits, they often identify molecules with functional groups that limit their utility as drugs. One prominent example is actinonin, an inhibitor of bacterial peptide deformylase (PDF) whose activity is dependent on a hydroxamate moiety associated with toxicity . The abundance of bacterial genomes now presents an opportunity for target-based natural product discovery, where biosynthetic pathways can be mined for molecules that possess desired activities but lack known pharmacophores. Here, we use bioinformatics to lead a chemotype-sensitive, target-based search for natural product inhibitors of bacterial PDF that lack the conserved metal chelating group. We describe the discovery, heterologous expression, biosynthesis, total synthesis, and activity of the gammanonins: actinonin homologues from Gammaproteobacteria. Moving forward, we hope this chemotype- and target-driven approach will help to expedite the discovery of new leads for antibiotic development.
抗生素对现代医学至关重要，但其使用推动了抗菌药物耐药性（AMR）的演变，这限制了任何一种药物的长期疗效。为了跟上AMR的步伐并保持我们治疗细菌感染的能力，识别具有不受临床耐药性影响的新结构和靶点的抗生素至关重要。从历史上看，大多数抗生素开发候选药物都来自微生物天然产物，因为它们具有经过数百万年进化锤炼的化学结构和生物活性。不幸的是，由于用于天然产物发现的经典生物活性筛选对其命中物的药理特性视而不见，它们经常鉴定出具有限制其作为药物用途的官能团的分子。一个突出的例子是放线宁，一种细菌肽脱甲酰基酶（PDF）的抑制剂，其活性取决于与毒性相关的异羟肟酸部分。现在大量的细菌基因组为基于靶点的天然产物发现提供了机会，在这种方法中，可以挖掘生物合成途径以寻找具有所需活性但缺乏已知药效团的分子。在这里，我们使用生物信息学进行基于化学型敏感、基于靶点的搜索，以寻找缺乏保守金属螯合基团的细菌PDF天然产物抑制剂。我们描述了γ-诺宁的发现、异源表达、生物合成、全合成和活性：来自γ-变形菌的放线宁同系物。展望未来，我们希望这种化学型和靶点驱动的方法将有助于加速抗生素开发新先导物的发现。
