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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.

Infectious diseases are a major cause of morbidity and mortality worldwide, exacerbated by increasing antibiotic resistance in many bacterial species. The development of drugs with new modes of action is essential. A leading strategy is antivirulence, with the aim to target bacterial proteins that are important in disease causation and progression but do not affect growth, resulting in reduced selective pressure for resistance. Immunophilins, a superfamily of peptidyl-prolyl cis - trans isomerase (PPIase) enzymes have been shown to be important for virulence in a broad-spectrum of pathogenic bacteria. This Perspective will provide an overview of the recent advances made in understanding the role of each immunophilin family, cyclophilins, FK506 binding proteins (FKBPs), and parvulins in bacteria. Inhibitor design and medicinal chemistry strategies for development of novel drugs against bacterial FKBPs will be discussed. Furthermore, drugs against human cyclophilins and parvulins will be reviewed in their current indication as antiviral and anticancer therapies.