Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA.
Department of Biology, University of Alabama in Huntsville, Huntsville, AL 35899, USA.
Molecules. 2021 Apr 15;26(8):2281. doi: 10.3390/molecules26082281.
With the relentless development of drug resistance and re-emergence of many pathogenic bacteria, the need for new antibiotics and new antibiotic targets is urgent and growing. Bacterial peptidyl-tRNA hydrolase, Pth1, is emerging as a promising new target for antibiotic development. From the conserved core and high degree of structural similarity, broad-spectrum inhibition is postulated. However, Pth1 small-molecule inhibition is still in the earliest stages. Focusing on pathogenic bacteria, herein we report the phylogenetic classification of Pth1 and natural product inhibition spanning phylogenetic space. While broad-spectrum inhibition is found, narrow-spectrum and even potentially clade-specific inhibition is more frequently observed. Additionally reported are enzyme kinetics and general in vitro Pth1 solubility that follow phylogenetic boundaries along with identification of key residues in the gate loop region that appear to govern both. The studies presented here demonstrate the sizeable potential for small-molecule inhibition of Pth1, improve understanding of Pth enzymes, and advance Pth1 as a much-needed novel antibiotic target.
随着耐药性的不断发展和许多病原菌的再次出现，人们迫切需要新的抗生素和新的抗生素靶标。细菌肽基-tRNA 水解酶 Pth1 作为一种有前途的新型抗生素开发靶标正在出现。从保守的核心和高度的结构相似性来看，推测可以进行广谱抑制。然而，Pth1 小分子抑制仍处于早期阶段。本文聚焦于病原菌，报告了 Pth1 的系统发育分类以及跨系统发育空间的天然产物抑制。虽然发现了广谱抑制，但更常见的是窄谱甚至潜在的进化枝特异性抑制。此外，还报告了酶动力学和一般体外 Pth1 溶解度，它们沿着系统发育边界进行，同时鉴定出门控环区域中的关键残基，这些残基似乎都对它们进行了控制。本文研究表明，小分子抑制 Pth1 的潜力巨大，提高了对 Pth 酶的认识，并推进了 Pth1 作为急需的新型抗生素靶标。
