Department of Biology, Brandeis University, Waltham, Massachusetts, USA.
Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
Antimicrob Agents Chemother. 2017 Sep 22;61(10). doi: 10.1128/AAC.00939-17. Print 2017 Oct.
is the causative agent of tularemia and a potential biowarfare agent. The virulence of is decreased by deletion of , the gene encoding IMP dehydrogenase (IMPDH), suggesting that this enzyme is a target for antibacterial design. Here we report that growth is blocked by inhibitors of bacterial IMPDHs. Seventeen compounds from two different frameworks, designated the D and Q series, display antibacterial activities with MICs of <1 μM. These compounds are also active against intracellular infections. Surprisingly, antibacterial activity does not correlate with IMPDH inhibition. In addition, the presence of guanine does not affect the antibacterial activity of most compounds, nor does the deletion of These observations suggest that antibacterial activity derives from inhibition of another target(s). Moreover, D compounds display antibacterial activity only against , suggesting the presence of a unique target or uptake mechanism. A Δ mutant resistant to compound D73 contained a missense mutation (Gly45Cys) in , which encodes a subunit of bacterial complex I. Overexpression of the mutant conferred resistance to D73 in both wild-type and Δ strains. This strain was not resistant to Q compounds, suggesting that a different off-target mechanism operates for these compounds. Several Q compounds are also effective against , in which a second target has also been implicated, in addition to IMPDH. The fortuitous presence of multiple targets with overlapping structure-activity relationships presents an intriguing opportunity for the development of robust antibiotics that may avoid the emergence of resistance.
是土拉热弗朗西斯菌的病原体，也是一种潜在的生物战剂。通过缺失编码 IMP 脱氢酶（IMPDH）的基因 ，可以降低 的毒力，这表明该酶是抗菌设计的靶标。本文报道了细菌 IMPDH 抑制剂可阻断 的生长。两种不同骨架的 17 种化合物，分别命名为 D 和 Q 系列，显示出 MIC 小于 1 μM 的抗菌活性。这些化合物也对细胞内感染具有活性。令人惊讶的是，抗菌活性与 IMPDH 抑制无关。此外，鸟嘌呤的存在并不影响大多数化合物的抗菌活性，也不会影响 的缺失。这些观察结果表明，抗菌活性源自对其他靶标（多个靶标）的抑制。此外，D 类化合物仅对 具有抗菌活性，表明存在独特的靶标或摄取机制。对化合物 D73 具有抗性的 Δ 突变体含有一个错义突变（Gly45Cys），该突变位于编码细菌复合物 I 亚基的 基因中。在野生型和 Δ 菌株中过表达 突变体均可赋予对 D73 的抗性。该菌株对 Q 类化合物不具有抗性，这表明这些化合物的作用机制不同。几种 Q 类化合物对 也有效，除了 IMPDH 之外，还涉及到第二个靶标。具有重叠结构-活性关系的多个靶标的偶然存在为开发可能避免耐药性产生的稳健抗生素提供了一个有趣的机会。
