Bryan Eric J, Qiao Qi, Wang Yuxuan, Roberge Jacques Y, LaVoie Edmond J, Pilch Daniel S
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Department of Molecular Design and Synthesis, Rutgers University Biomedical Innovation Cores, Piscataway, NJ 08854, USA.
Antibiotics (Basel). 2024 Feb 22;13(3):209. doi: 10.3390/antibiotics13030209.
The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor () that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that is active against both and , with this activity being dependent on direct Fe chelation and enhanced under Fe-limiting conditions. Genetic deletion studies in reveal that gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that exhibits bactericidal synergy against when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting β-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance.
多重耐药革兰氏阴性菌病原体构成的全球威胁使得开发新型有效抗生素成为必要。FtsZ是一种必需且高度保守的细胞骨架蛋白，是新型抗菌疗法颇具吸引力的抗菌靶点。然而，FtsZ抑制剂对革兰氏阴性菌的有效性有限，部分原因是细胞内积累不佳。为解决这一限制，我们设计了一种FtsZ抑制剂（），其包含一种氯邻苯二酚铁载体功能基团，该基团可螯合三价铁（Fe），并利用内源性铁载体摄取途径促进进入革兰氏阴性病原体。我们表明，对和均有活性，这种活性依赖于直接的铁螯合作用，且在铁限制条件下增强。在中的基因缺失研究表明，通过FepA和CirA外膜转运蛋白以及FhuBC内膜转运蛋白进入。我们还表明，与选定抗生素联合使用时，对表现出杀菌协同作用，与靶向PBP2的β-内酰胺类药物或MreB抑制剂联合观察到最强的协同作用。总体而言，我们的研究表明，将铁螯合部分引入FtsZ抑制剂是一种增强对具有全球临床意义的革兰氏阴性病原体活性的有吸引力的设计策略。
