Targeting Protein Folding: A Novel Approach for the Treatment of Pathogenic Bacteria

Abstract

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.

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

“…6,[11][12][13][14] Microbial or parasitic FKBPs (sometimes also called Macrophage infectivity potentiators, Mips) are important for replication of the pathogens and FKBP/Mip inhibitors in turn have anti-infective potential. 15 Finally, FKBPs are the key enabling adaptors for the clinically approved immunosuppressants FK506 and rapamycin as well as for several recently identied molecular glues. [16][17][18][19][20][21][22] Previously, we developed bicyclic [4.3.1] sulfonamides, [23][24][25][26][27] which mimic the core of the natural products FK506 and rapamycin, retain the anti-infective 23 and BMP-stimulating properties 6,10 of these natural products, but lack their immunosuppressive properties.…”

“…However, the shallow FKBP binding site generally makes the development of ligands with drug-like properties challenging. 7,15,28 Here, we exploit the dened rigid architecture of the bicyclic scaffold to strategically install a solvent exposed chiral methyl group that displaces a conserved water molecule, robustly leading to a boost in binding affinity to FK506-binding proteins (FKBPs).…”

Protein sociology of ProA, Mip and other secreted virulence factors at the Legionella pneumophila surface

“…The fold of the Cterminal domain (residues 100-213) shows high homology to the human FK506-binding protein 12 (FKBP12) (Schmidt et al, 1996;Fischer et al, 1998), and the macrolides FK506 or rapamycin efficiently inhibit the PPIase activity of the respective proteins (Schiene-Fischer et al, 2013). Further Mip targeting inhibitors such as cycloheximide, pipecolic acid, as well as nonimmunosuppressive FK506 derivatives independently corroborated the observation of moonlighting activities of Mip in fundamental processes of infection (Scheuplein et al, 2020;Rasch et al, 2015;Rasch et al, 2014;Juli et al, 2011;Pomplun et al, 2018;.…”

Legionella pneumophilamacrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding

“…[22], Neisseria gonorrhoeae [23], the entero-pathogen Salmonella typhimurium [24], Pseudomonas aeruginosa [25], and intracellular parasitic protozoans such as Trypanosoma cruzi, the causative agent of Chagas disease in South and Central America [26][27][28]. Hence, the PPIase domains of MIP proteins are attractive antimicrobial and antiparasitic drug targets [29], however their shallow ligand binding pocket and similarity to human FKBPs render selective drug design challenging [30,31]. No structures of a Legionella MIP with a synthetic inhibitor are available to date and, in the absence of a high-resolution structure of a microbial MIP and human FKBP MIP in complex with the same synthetic inhibitor, no side-by-side structural comparison is currently possible.…”