TY - JOUR
T1 - Analysis of Structure-Activity Relationships of Novel Inhibitors of the Macrophage Infectivity Potentiator (Mip) Proteins of Neisseria meningitidis, Neisseria gonorrhoeae, and Burkholderia pseudomallei
AU - Scheuplein, Nicolas J
AU - Bzdyl, Nicole M
AU - Lohr, Theresa
AU - Kibble, Emily A
AU - Hasenkopf, Anja
AU - Herbst, Carina
AU - Sarkar-Tyson, Mitali
AU - Holzgrabe, Ulrike
PY - 2023/7/13
Y1 - 2023/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164457005&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c00458
DO - 10.1021/acs.jmedchem.3c00458
M3 - Article
C2 - 37389560
SN - 0022-2623
VL - 66
SP - 8876
EP - 8895
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -