Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States.
Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
J Med Chem. 2017 Jun 8;60(11):4577-4583. doi: 10.1021/acs.jmedchem.7b00102. Epub 2017 Apr 1.
In order to address the dire need for new antibiotics to treat specific strains of drug resistant Gram-negative bacterial infections, a mixed ligand analog of the natural Acinetobacter baumannii selective siderophore, fimsbactin, was coupled to daptomycin, a Gram-positive only antibiotic. The resulting conjugate 11 has potent activity against multidrug resistant strains of A. baumannii both in vitro and in vivo. The study also indicates that conjugation of siderophores to "drugs" that are much larger than the siderophore (iron transport agent) itself facilitates active uptake that circumvents the normal permeability problems in Gram-negative bacteria. The results demonstrate the ability to extend activity of a normally Gram-positive only antibiotic to create a potent and targeted Gram-negative antibiotic using a bacterial iron transport based sideromycin Trojan horse strategy.
为了解决治疗特定耐药革兰氏阴性菌感染的新型抗生素的迫切需求，将天然鲍曼不动杆菌选择性铁载体的混合配体类似物 fimsbactin 与仅针对革兰氏阳性菌的抗生素达托霉素偶联。所得的缀合物 11 在体外和体内均对多药耐药的鲍曼不动杆菌菌株具有很强的活性。该研究还表明，将铁载体与比铁载体（铁转运剂）本身大得多的“药物”偶联，有助于主动摄取，从而规避革兰氏阴性菌中常见的通透性问题。结果表明，能够将一种通常仅对革兰氏阳性菌有效的抗生素的活性扩展，从而利用基于细菌铁转运的铁载体木马策略创建一种有效的靶向革兰氏阴性菌的抗生素。
