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

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.