McPherson Jacob K, Hurdle Julian G, Baker Matthew L, Hussain Tahir, Kumar Ashok, Garey Kevin W
Department of Pharmacy Practice and Translational Research, University of Houston, Houston, Texas, USA.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas, USA.
Antimicrob Agents Chemother. 2025 Apr 2;69(4):e0167924. doi: 10.1128/aac.01679-24. Epub 2025 Feb 21.
Ibezapolstat (IBZ), a first-in-class antibiotic targeting the PolC-type DNA polymerase III alpha-subunit (PolC) in low G + C bacteria, is in clinical development for the treatment of infection (CDI). In the phase 2 trials, IBZ had potent activity against while sparing or causing regrowth of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichales, common commensal low G + C bacteria. The purpose of this study was to utilize approaches to better interpret the narrower than expected IBZ spectrum of activity. IBZ susceptibility to human commensal microbiota was predicted using genomic analysis and PolC phylogenetic tree construction in relation to and commensal low G + C bacteria. Protein structure prediction was performed using AlphaFold2 and binding pocket homology modeling was performed using Schrodinger Maestro and UCSF ChimeraX. An amino acid phylogenetic tree identified certain residues that were phylogenetically variant in Lachnospiraceae, Oscillospiraceae, and Erysipelotrichales and conserved in . Chemical modeling showed that these residues ablated key PolC•IBZ predicted interactions including two lysine "" (Lys1148 and Lys1327) that "" onto the compound; an "" interaction (Thr1331) to the central moiety; and a stabilized set of sensitizer residues (Thr1291 and Lys1292) that resulted in the prolonged inhibition of a catalytic residue (Asp1090). The observed IBZ sparing of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichaceae/Coprobacillaceae was predicted using techniques. Further studies that confirm a PolC structural basis for the IBZ narrower than expected activity are needed to confirm these phylogenetic and chemical modeling data.
伊贝扎泊司他（IBZ）是一种针对低G+C细菌中PolC型DNA聚合酶IIIα亚基（PolC）的首创抗生素，目前正处于治疗艰难梭菌感染（CDI）的临床开发阶段。在2期试验中，IBZ对艰难梭菌具有强大的活性，同时保留或导致毛螺菌科、颤螺菌科和丹毒丝菌目等常见共生低G+C细菌重新生长。本研究的目的是利用多种方法更好地解释IBZ活性谱比预期更窄的现象。通过基因组分析和与艰难梭菌及共生低G+C细菌相关的PolC系统发育树构建，预测了IBZ对人类共生微生物群的敏感性。使用AlphaFold2进行蛋白质结构预测，并使用薛定谔Maestro和加州大学旧金山分校ChimeraX进行结合口袋同源建模。氨基酸系统发育树确定了某些在毛螺菌科、颤螺菌科和丹毒丝菌目中具有系统发育变异且在艰难梭菌中保守的残基。化学建模表明，这些残基消除了关键的PolC•IBZ预测相互作用，包括两个与化合物结合的赖氨酸（Lys1148和Lys1327）；与中心部分的“特定相互作用”（Thr1331）；以及一组稳定的敏化剂残基（Thr1291和Lys1292），这些残基导致催化残基（Asp1090）的抑制时间延长。使用多种技术预测了观察到的IBZ对毛螺菌科、颤螺菌科和丹毒丝菌科/粪杆菌科的保留情况。需要进一步的研究来证实IBZ活性比预期更窄的PolC结构基础，以确认这些系统发育和化学建模数据。
