PDF(Pubmed)
Abstract：
Selective drugs with a relatively narrow spectrum can reduce the side effects of treatments compared to broad-spectrum antibiotics by specifically targeting the pathogens responsible for infection. Furthermore, combating an infectious pathogen, especially a drug-resistant microorganism, is more efficient by attacking multiple targets. Here, we combined synthetic lethality with selective drug targeting to identify multi-target and organism-specific potential drug candidates by systematically analyzing the genome-scale metabolic models of six different microorganisms. By considering microorganisms as targeted or conserved in groups ranging from one to six members, we designed 665 individual case studies. For each case, we identified single essential reactions as well as double, triple, and quadruple synthetic lethal reaction sets that are lethal for targeted microorganisms and neutral for conserved ones. As expected, the number of obtained solutions for each case depends on the genomic similarity between the studied microorganisms. Mapping the identified potential drug targets to their corresponding pathways highlighted the importance of key subsystems such as cell envelope biosynthesis, glycerophospholipid metabolism, membrane lipid metabolism, and the nucleotide salvage pathway. To assist in the validation and further investigation of our proposed potential drug targets, we introduced two sets of targets that can theoretically address a substantial portion of the 665 cases. We expect that the obtained solutions provide valuable insights into designing narrow-spectrum drugs that selectively cause system-wide damage only to the target microorganisms.
摘要：
与广谱抗生素相比，具有相对窄谱的选择性药物可以通过特异性靶向引起感染的病原体来减少治疗的副作用。此外，对抗传染性病原体，尤其是耐药微生物，通过攻击多个目标更有效。这里,我们通过系统分析6种不同微生物的基因组尺度代谢模型,将合成致死性与选择性药物靶向相结合,以鉴定多靶点和生物体特异性的潜在候选药物.通过将微生物视为靶向的或保守的，在一到六个成员的群体中，我们设计了665个案例研究。对于每种情况，我们确定了单一的基本反应以及双重反应，三重，和四重合成致死反应集，对目标微生物是致死的，对保守微生物是中性的。不出所料,每种情况下获得的解决方案的数量取决于所研究微生物之间的基因组相似性。将确定的潜在药物靶标映射到其相应的途径，突出了关键子系统的重要性，如细胞包膜生物合成。甘油磷脂代谢，膜脂代谢，和核苷酸补救途径。为了协助验证和进一步调查我们提出的潜在药物靶点，我们引入了两组目标，理论上可以解决665例病例中的很大一部分。我们期望所获得的解决方案为设计窄谱药物提供了有价值的见解，这些药物选择性地仅对目标微生物造成全系统损害。
