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Comparative Genomic Assessment of Novel Broad-Spectrum Targets for Antibacterial Drugs

机译：新型抗菌药物广谱靶标的基因组比较评估

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Single and multiple resistance to antibacterial drugs currently in use is spreading,since they act against only a very small number of molecular targets; finding noveltargets for anti-infectives is therefore of great importance. All protein sequences fromthree pathogens (Staphylococcus aureus, Mycobacterium tuberculosisandEscherichia coliO157:H7 EDL993) were assessed via comparative genomics methods for theirsuitability as antibacterial targets according to a number of criteria, including theessentiality of the protein, its level of sequence conservation, and its distribution inpathogens, bacteria and eukaryotes (especially humans). Each protein was scored andranked based on weighted variants of these criteria in order to prioritize proteins aspotential novel broad-spectrum targets for antibacterial drugs. A number of proteinsproved to score highly in all three species and were robust to variations in the scoringsystem used. Sensitivity analysis indicated the quantitative contribution of each metricto the overall score. After further analysis of these targets, tRNA methyltransferase(trmD) and translation initiation factor IF-1 (infA) emerged as potential and novelantimicrobial targets very worthy of further investigation. The scoring strategy usedmight be of value in other areas of post-genomic drug discovery.
机译：目前正在使用的对抗菌药物的单一和多重耐药性正在扩大，因为它们仅针对极少数的分子靶标起作用;因此，寻找新的抗感染目标非常重要。通过比较基因组学方法评估了三种病原体（金黄色葡萄球菌，结核分枝杆菌和大肠杆菌O157：H7 EDL993）的所有蛋白质序列是否适合作为抗菌靶标，包括蛋白质的必要性，其序列保守性水平及其病原体分布，细菌和真核生物（尤其是人类）。基于这些标准的加权变异对每种蛋白质进行评分和排名，以便优先将蛋白质作为抗菌药物的潜在新型广谱靶标。事实证明，许多蛋白质在这三个物种中均能获得高分，并且对所使用的评分系统的变异具有较强的抵抗力。敏感性分析表明每个指标对总分的定量贡献。在对这些靶标进行进一步分析后，tRNA甲基转移酶（trmD）和翻译起始因子IF-1（infA）成为潜在的和新型抗菌靶标，非常值得进一步研究。所采用的评分策略可能在基因组药物开发后的其他领域中具有价值。

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