Carfrae Lindsey A, Brown Eric D
Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, L8S 4L8, Canada; Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, L8S 4L8, Canada; Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8S 4L8, Canada; Present address: Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
Trends Microbiol. 2023 Jun;31(6):571-585. doi: 10.1016/j.tim.2023.01.002. Epub 2023 Jan 27.
Novel approaches are required to address the looming threat of pan-resistant Gram-negative pathogens and forestall the rise of untreatable infections. Unconventional targets that are uniquely important during infection and tractable to high-throughput drug discovery methods hold high potential for innovation in antibiotic discovery programs. In this context, inhibitors of bacterial nutrient stress are particularly exciting candidates for future antibiotic development. Amino acid, nucleotide, and vitamin biosynthesis pathways are critical for bacterial growth in nutrient-limiting conditions in the laboratory and the host. Although historically dismissed as dispensable for pathogens, a wealth of transposon mutagenesis and single-mutant studies have emerged which demonstrate that several such pathways are critical for infection. Indeed, high-throughput screens of diverse synthetic compounds and natural products have uncovered inhibitors of nutrient biosynthesis. Herein, we review bacterial nutrient biosynthesis and its role during host infection. Further, we explore screening platforms developed to search for inhibitors of these targets and highlight successes among these. Finally, we feature important and sometimes surprising connections between bacterial nutrient biosynthesis, antibiotic activity, and antibiotic resistance.
需要采用新方法来应对泛耐药革兰氏阴性病原体迫在眉睫的威胁，并防止出现无法治疗的感染。在感染过程中具有独特重要性且适用于高通量药物发现方法的非常规靶点，在抗生素发现计划中具有很高的创新潜力。在此背景下，细菌营养应激抑制剂是未来抗生素开发特别令人兴奋的候选物。氨基酸、核苷酸和维生素生物合成途径对于实验室和宿主体内营养限制条件下的细菌生长至关重要。尽管从历史上看，这些途径被认为对病原体来说是可有可无的，但大量转座子诱变和单突变研究表明，其中一些途径对感染至关重要。事实上，对各种合成化合物和天然产物的高通量筛选已经发现了营养生物合成的抑制剂。在此，我们综述细菌营养生物合成及其在宿主感染中的作用。此外，我们探索为寻找这些靶点的抑制剂而开发的筛选平台，并突出其中的成功案例。最后，我们重点介绍细菌营养生物合成、抗生素活性和抗生素耐药性之间重要且有时令人惊讶的联系。
