Analysis of Structure-Activity Relationships of Novel Inhibitors of the Macrophage Infectivity Potentiator (Mip) Proteins of Neisseria meningitidis, Neisseria gonorrhoeae, and Burkholderia pseudomallei

Nicolas J Scheuplein, Nicole M Bzdyl, Theresa Lohr, Emily A Kibble, Anja Hasenkopf, Carina Herbst, Mitali Sarkar-Tyson, Ulrike Holzgrabe

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

The macrophage infectivity potentiator (Mip) protein is a promising target for developing new drugs to combat antimicrobial resistance. New rapamycin-derived Mip inhibitors have been designed that may be able to combine two binding modes to inhibit the Mip protein of Burkholderia pseudomallei (BpMip). These novel compounds are characterized by an additional substituent in the middle chain linking the lateral pyridine to the pipecoline moiety, constituting different stereoisomers. These compounds demonstrated high affinity for the BpMip protein in the nanomolar range and high anti-enzymatic activity and ultimately resulted in significantly reduced cytotoxicity of B. pseudomallei in macrophages. They also displayed strong anti-enzymatic activity against the Mip proteins of Neisseria meningitidis and Neisseria gonorrhoeae and substantially improved the ability of macrophages to kill the bacteria. Hence, the new Mip inhibitors are promising, non-cytotoxic candidates for further testing against a broad spectrum of pathogens and infectious diseases.

Original languageEnglish
Pages (from-to)8876-8895
Number of pages20
JournalJournal of Medicinal Chemistry
Volume66
Issue number13
DOIs
Publication statusPublished - 13 Jul 2023

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