Pipecolic Acid Derivatives As Small-Molecule Inhibitors of the <i>Legionella</i> MIP Protein

Juli, Christina; Sippel, Martin; Jäger, Jens; Thiele, Alexandra; Weiwad, Matthias; Schweimer, Kristian; Rösch, Paul; Steinert, Michael; Sotriffer, Christoph A.; Holzgrabe, Ulrike

doi:10.1021/jm101156y

Cited by 48 publications

(65 citation statements)

References 18 publications

(43 reference statements)

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“…Colonies were visible on BCYE agar at 4 days after plating. Wild-type L. pneumophila multiplied by approximately 10-fold in 24 h, similarly to in previous studies in human macrophage-like cells (34). After 24 h, the bacterial load continued to increase at a lower rate.…”

Section: Pneumophila Causes Tissue Damage In Infected Human Lung Tsupporting

confidence: 85%

Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections

et al. 2014

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Histopathologically, Legionnaires' disease, caused by the Gram-negative bacterium Legionella pneumophila, is an acute fibrinopurulent pneumonia. Since the first documented outbreak of Legionnaires' disease in 1976, several autopsy series have been published (1). Samples from patients who died from L. pneumophila pneumonia exhibit a massive infiltration of neutrophils and macrophages into the alveoli and destruction of alveolar septa. Moreover, the alveolar epithelium shows sloughs, and inflammatory cells exhibit intense necrosis. L. pneumophila is present mainly in alveoli and tends to cluster inside macrophages. In late infection stages, bacteria disseminate to the patient's spleen, kidneys, bone marrow, and lymph nodes (1-4).Different models have been established to analyze specific aspects of infection. Besides human monocellular systems such as macrophages and epithelial cells, protozoa such as Acanthamoeba castellanii, Hartmannella vermiformis, and Dictyostelium discoideum were used to study the cellular and molecular pathogenicity of L. pneumophila (5-9). These studies revealed that L. pneumophila primarily enters phagocytes and resides within a unique membrane-bound compartment termed the Legionellacontaining vacuole (LCV). The establishment of this replication niche requires the translocation of about 300 effector proteins into the host cell via a functional Dot/Icm type IV secretion (10-12). Studying transcriptional responses of L. pneumophila-infected macrophages and D. discoideum vegetative cells also shed light on the cellular mechanisms of Legionnaires' disease (13-16). Moreover, proteomic approaches were shown to be powerful tools to characterize both sides of the host-pathogen interaction (17)(18)(19). Mammalian models such as guinea pigs, mice, rhesus monkeys, and marmosets were used to address immunological, pathological, and pharmacological questions (20)(21)(22). Despite providing enormous progress in the knowledge about mechanisms of L. pneumophila infections, each of the current infection models has intrinsic limitations. Cell culture assays lack the complex interaction networks between the specialized cell types and extracellular components in the human lung. Guinea pig infections require intraperitoneal or intratracheal inoculation techniques, and owing to a different genetic and immunological background, the adequacy and transferability to humans can be questioned.Given the different model-immanent limitations, numerous intra-and extracellular interactions of L. pneumophila factors with human lung tissue structures remain unknown. For example, early infection events appear to be underexplored, since histopathology studies were performed postmortem. Even conspicuous subcellular structures, such as the abundant outer membrane vesicles (OMVs) shed by L. pneumophila, have not yet been investigated in human lung tissue. OMVs contain large amounts of degradative enzymes and other virulence-related proteins, which

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Section: Pneumophila Causes Tissue Damage In Infected Human Lung Tsupporting

confidence: 85%

Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections

et al. 2014

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“…This work describes our initial efforts to design and characterize small lead-like molecules that can influence the virulence of B. pseudomallei through BpML1 inhibition without compromising host immunity. Through synthetic variation and testing, we replaced the anchoring moiety in known macrocyclic inhibitors with a select set of small-molecule pipecolic acid derivatives, forming an important anchoring scaffold (24,25). We obtained cocrystallization structures to demonstrate that BpML1 binds to our pipecolic acid derivatives in a manner analogous to the piperidine moieties of macrocyclic FK506 (26,27) and rapamycin (28), allowing identification of the essential chemical scaffold necessary for binding.…”

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confidence: 99%

A Structural Biology Approach Enables the Development of Antimicrobials Targeting Bacterial Immunophilins

Begley¹,

Fox²,

Jenner

et al. 2014

Antimicrob Agents Chemother

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f Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery.

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“…The (S)-enantiomer of structure B containing the less bulky sulfonamide fitted much better into the hydrophobic pocket of Mip (Fig. 1A) (Juli et al, 2011).…”

Section: Pipecolinic Acid Derivativesmentioning

confidence: 98%

“…Interestingly, treating U397 macrophage-like cells that were infected with L. pneumophila with 50 µM S-4c had no detrimental effect on the infection. The authors concluded from this that properties other than the PPIase activity of the Mip protein determined its virulence characteristics (Juli et al, 2011).…”

Section: Pipecolinic Acid Derivativesmentioning

confidence: 99%

“…Recently, small molecule inhibitors based on this core inhibitory structure were tested on Mip and BpML1 (Begley et al, 2014;Juli et al, 2011). In order to find novel inhibitors of Mip, two previously reported pipecoline ring containing inhibitors A and B with K i (app) of 10 nM and 0.23 µM, respectively, were used as lead structures.…”

Section: Pipecolinic Acid Derivativesmentioning

confidence: 99%

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FKBPs in bacterial infections

Ünal

Steinert

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Pipecolic Acid Derivatives As Small-Molecule Inhibitors of the Legionella MIP Protein

Cited by 48 publications

References 18 publications

Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections

Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections

A Structural Biology Approach Enables the Development of Antimicrobials Targeting Bacterial Immunophilins

FKBPs in bacterial infections

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