Novel Cycloheximide Derivatives Targeting the Moonlighting Protein Mip Exhibit Specific Antimicrobial Activity Against Legionella pneumophila

Rasch, Janine; Theuerkorn, Martin; Ünal, Can; Heinsohn, Natascha; Tran, Stefan; Fischer, Gunter; Weiwad, Matthias; Steinert, Michael

doi:10.3389/fbioe.2015.00041

Cited by 19 publications

(20 citation statements)

References 36 publications

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“…These derivatives displayed lower IC 50 values and improved selectivity for MIP (although FKBP12 was still 10-fold better inhibited) and inhibited bacterial growth in liquid culture. Notably, the effect was independent of MIP, since the same effect was shown in Δ mip -mutants (Rasch et al, 2015).…”

Section: Microbial Fkbpsmentioning

confidence: 70%

FKBP Ligands—Where We Are and Where to Go?

et al. 2018

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In recent years, many members of the FK506-binding protein (FKBP) family were increasingly linked to various diseases. The binding domain of FKBPs differs only in a few amino acid residues, but their biological roles are versatile. High-affinity ligands with selectivity between close homologs are scarce. This review will give an overview of the most prominent ligands developed for FKBPs and highlight a perspective for future developments. More precisely, human FKBPs and correlated diseases will be discussed as well as microbial FKBPs in the context of anti-bacterial and anti-fungal therapeutics. The last section gives insights into high-affinity ligands as chemical tools and dimerizers.

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Section: Microbial Fkbpsmentioning

confidence: 70%

FKBP Ligands—Where We Are and Where to Go?

et al. 2018

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“…Infection of a THP-1 macrophage-like cell line with L. pneumophila. To analyze the intracellular replication of L. pneumophila mutant strains in human macrophages, the acute monocytic leukemia cell line THP-1 (DSMZ ACC16) was used (59). The cells were adjusted to 5 ϫ 10 5 cells/ml in cell culture medium (RPMI 1640, 2 mM L-glutamine, 10% fetal calf serum [FCS]) supplemented with 100 nM phorbol-12-myristate-13-acetate (PMA) for differentiation into macrophage-like cells.…”

Section: Methodsmentioning

confidence: 99%

Peptidyl-Prolyl- cis / trans -Isomerases Mip and PpiB of Legionella pneumophila Contribute to Surface Translocation, Growth at Suboptimal Temperature, and Infection

et al. 2019

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The gammaproteobacterium Legionella pneumophila is the causative agent of Legionnaires’ disease, an atypical pneumonia that manifests itself with severe lung damage. L. pneumophila, a common inhabitant of freshwater environments, replicates in free-living amoebae and persists in biofilms in natural and man-made water systems. Its environmental versatility is reflected in its ability to survive and grow within a broad temperature range as well as its capability to colonize and infect a wide range of hosts, including protozoa and humans. Peptidyl-prolyl-cis/trans-isomerases (PPIases) are multifunctional proteins that are mainly involved in protein folding and secretion in bacteria. In L. pneumophila the surface-associated PPIase Mip was shown to facilitate the establishment of the intracellular infection cycle in its early stages. The cytoplasmic PpiB was shown to promote cold tolerance. Here, we set out to analyze the interrelationship of these two relevant PPIases in the context of environmental fitness and infection. We demonstrate that the PPIases Mip and PpiB are important for surfactant-dependent sliding motility and adaptation to suboptimal temperatures, features that contribute to the environmental fitness of L. pneumophila. Furthermore, they contribute to infection of the natural host Acanthamoeba castellanii as well as human macrophages and human explanted lung tissue. These effects were additive in the case of sliding motility or synergistic in the case of temperature tolerance and infection, as assessed by the behavior of the double mutant. Accordingly, we propose that Mip and PpiB are virulence modulators of L. pneumophila with compensatory action and pleiotropic effects.

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“…124 Recently, this work has been expanded to test the cycloheximide scaffold and its derivatives as novel antibacterial agents. 125 …”

Section: Inhibitors Of Fkbpsmentioning

confidence: 99%

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

2016

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Peptidyl-proline isomerases (PPIases) are a chaperone superfamily comprising the FK506-binding proteins (FKBPs), cyclophilins, and parvulins. PPIases catalyze the cis/trans isomerization of proline, acting as a regulatory switch during folding, activation, and/or degradation of many proteins. These “clients” include proteins with key roles in cancer, neurodegeneration, and psychiatric disorders, suggesting that PPIase inhibitors could be important therapeutics. However, the active site of PPIases is shallow, solvent-exposed, and well conserved between family members, making selective inhibitor design challenging. Despite these hurdles, macrocyclic natural products, including FK506, rapamycin, and cyclosporin, bind PPIases with nanomolar or better affinity. De novo attempts to derive new classes of inhibitors have been somewhat less successful, often showcasing the “undruggable” features of PPIases. Interestingly, the most potent of these next-generation molecules tend to integrate features of the natural products, including macrocyclization or proline mimicry strategies. Here, we review recent developments and ongoing challenges in the inhibition of PPIases, with a focus on how natural products might inform the creation of potent and selective inhibitors.

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Novel Cycloheximide Derivatives Targeting the Moonlighting Protein Mip Exhibit Specific Antimicrobial Activity Against Legionella pneumophila

Cited by 19 publications

References 36 publications

FKBP Ligands—Where We Are and Where to Go?

FKBP Ligands—Where We Are and Where to Go?

Peptidyl-Prolyl- cis / trans -Isomerases Mip and PpiB of Legionella pneumophila Contribute to Surface Translocation, Growth at Suboptimal Temperature, and Infection

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

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