Inhibitors of macrophage infectivity potentiator-like PPIases affect neisserial and chlamydial pathogenicity

Reimer, Anastasija; Seufert, Florian; Weiwad, Matthias; Ebert, J.; Bzdyl, Nicole M.; Kahler, Charlene M.; Sarkar‐Tyson, Mitali; Holzgrabe, Ulrike; Rudel, Thomas; Kozjak-Pavlovic, Vera

doi:10.1016/j.ijantimicag.2016.06.020

Cited by 26 publications

(39 citation statements)

References 38 publications

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“…Although one compound displayed high activity against the FKBP domain of Legionella MIP (IC 50 = 6 μM), no influence on the replication of L. pneumophila in human cells was observed (Juli et al, 2011). Subsequent improved analogs, however, inhibited replication of Chlamydia trachomatis and reduced intracellular survival of Neisseria species (Reimer et al, 2016; Seufert et al, 2016). Recently, Pomplun et al developed bicyclic ligands with high affinities for microbial FKBPs and MIPs (Ligands 4 , 5 , and 6 , Figure 8), including Plasmodium falciparum, Legionella pneumophila as well as Chlamydia pneumoniae and trachomatis .…”

Section: Microbial Fkbpsmentioning

confidence: 99%

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: 99%

FKBP Ligands—Where We Are and Where to Go?

et al. 2018

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“…A Neisseria gonorrhoeae MIP homologue was required for intramacrophage survival 51,52 and a Neisseria meningitidis MIP homologue was important for meningococcal survival in the blood 53 . Furthermore, inhibition of Nm-MIP prevented meningococci from adhering, invading and/or surviving in epithelial cells 54 . Several bacteria that cause animal infections, including Chlamydia, Francisella, Aeromonas and Pseudoalteromonas , amongst many others, also produce MIP-like PPIases essential for virulence 25 .…”

Section: Discussionmentioning

confidence: 95%

Characterization of two putative Dichelobacter nodosus footrot vaccine antigens identifies the first lysozyme inhibitor in the genus

Humbert

Jackson

Orr

et al. 2019

Sci Rep

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The Gram-negative anaerobic bacterium Dichelobacter nodosus (Dn) causes footrot in ruminants, a debilitating and highly contagious disease that results in necrotic hooves and significant economic losses in agriculture. Vaccination with crude whole-cell vaccine mixed with multiple recombinant fimbrial proteins can provide protection during species-specific outbreaks, but subunit vaccines containing broadly cross-protective antigens are desirable. We have investigated two D. nodosus candidate vaccine antigens. Macrophage Infectivity Potentiator Dn-MIP (DNO_0012, DNO_RS00050) and Adhesin Complex Protein Dn-ACP (DNO_0725, DNO_RS06795) are highly conserved amongst ~170 D. nodosus isolates in the https://pubmlst.org/dnodosus/ database. We describe the presence of two homologous ACP domains in Dn-ACP with potent C-type lysozyme inhibitor function, and homology of Dn-MIP to other putative cell-surface and membrane-anchored MIP virulence factors. Immunization of mice with recombinant proteins with a variety of adjuvants induced antibodies that recognised both proteins in D. nodosus . Notably, immunization with fimbrial-whole-cell Footvax vaccine induced anti-Dn-ACP and anti-Dn-MIP antibodies. Although all adjuvants induced high titre antibody responses, only antisera to rDn-ACP-QuilA and rDn-ACP-Al(OH) 3 significantly prevented rDn-ACP protein from inhibiting lysozyme activity in vitro . Therefore, a vaccine incorporating rDn-ACP in particular could contribute to protection by enabling normal innate immune lysozyme function to aid bacterial clearance.

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“…Neisseria MIP proteins are potential targets for drug therapies during infection [15] and for the development of prophylactic vaccines [13] . Our data demonstrate the reproducibility of independent vaccines batches for generating bactericidal antibodies against a panel of homologous and heterologous MIP Type and serogroup meningococci, and cross-reactive with some gonococcal strains.…”

Section: Discussionmentioning

confidence: 99%

“…A possible candidate for inclusion in new vaccines is the Macrophage Infectivity Potentiator protein (MIP, NMB1567/NEIS1487), which is a member of the FK506-binding protein (FKBP)-type peptidyl prolyl cis/trans isomerase (PPIase) family of proteins [12] , [13] . Expression of the nm-mip gene was important for meningococcal survival in the blood [13] , [14] and inhibition of Nm-MIP prevented meningococci from adhering, invading and/or surviving in epithelial cells [15] . Nm-MIP is highly conserved and expressed by all meningococcal strains reported to date, is outer membrane (OM)-located, surface exposed and capable of inducing cross-protective bactericidal antibodies [13] , [16] , [17] .…”

Section: Introductionmentioning

confidence: 99%