Bacterial serine protease HtrA as a promising new target for antimicrobial therapy?
© The Author(s). 2017
Received: 21 December 2016
Accepted: 4 January 2017
Published: 10 January 2017
Recent studies have demonstrated that the bacterial chaperone and serine protease high temperature requirement A (HtrA) is closely associated with the establishment and progression of several infectious diseases. HtrA activity enhances bacterial survival under stress conditions, but also has direct effects on functions of the cell adhesion protein E-cadherin and extracellular matrix proteins, including fibronectin and proteoglycans. Although HtrA cannot be considered as a pathogenic factor per se, it exhibits favorable characteristics making HtrA a potentially attractive drug target to combat various bacterial infections.
(Patho)-physiological function of bacterial HtrA
Until recently, it has been commonly accepted that HtrA family members of bacteria are strictly acting inside the periplasm. However, we have recently unraveled a hitherto unknown function of HtrA during bacterial infection. Campylobacter jejuni and its close relative Helicobacter pylori actively secrete HtrA proteins in the extracellular environment, where they target host cell factors [19–21]. HtrA was also identified in outer membrane vesicles released by C. jejuni, H. pylori, Vibrio cholera, Chlamydia muridarum or Borrelia burgdorferi [22–26]. Infection experiments with polarized cell monolayers in vitro suggested that H. pylori and C. jejuni HtrA can disrupt the epithelial barrier by opening cell-to-cell junctions. This remarkable effect is achieved by cleaving-off the extracellular domain of the surface adhesion protein and tumor suppressor E-cadherin, and probably other junctional proteins by HtrA, followed by paracellular bacterial transmigration [20, 21]. The deletion of the htrA gene in C. jejuni led to a defect in E-cadherin shedding and causes impaired transmigration of the bacteria across monolayers of polarized epithelial cells in vitro [19, 21].
In particular, E-cadherin showed to be an important factor for establishing and maintaining epithelial integrity in the host. E-cadherin is a single transmembrane protein, which consists of an intracellular domain (IC), a transmembrane domain (TD), and five extracellular domains (EC) . EC domains establish homophilic interactions in cis and trans that require calcium binding to the linker region between the EC domains. We have recently identified the cleavage sites of H. pylori HtrA in E-cadherin. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern as preferentially cleaved by HtrA . The results of our studies also suggest that the presence of calcium ions blocks HtrA-mediated cleavage by interfering with the accessibility of calcium-binding regions between the individual EC domains harboring the HtrA cleavage sites . Investigating C. jejuni ΔhtrA deletion mutants in in vivo studies, it was demonstrated that HtrA plays a crucial role during infection by triggering host cell apoptosis and immunopathology in mice [30, 31]. Similarly, HtrA is critical for the virulence of many other pathogens including Brucella abortus , Yersinia enterocolitica , Salmonella enterica , Legionella pneumophila , Shigella flexneri , Klebsiella pneumoniae , Listeria monocytogenes , Burkholderia cenocepacia , Chlamydia trachomatis , Borrelia burgdorferi , Mycobacterium tuberculosis  and Haemophilus parasuis . In contrast, the deletion of the htrA gene in H. pylori has not yet been reported, and the generation of ΔhtrA knockout mutants was found to be lethal [40, 41]. Given the fact that H. pylori htrA is an essential bifunctional gene with crucial intracellular and extracellular functions, it may be justified to consider HtrA as a new target for future anti-bacterial therapy.
Why is HtrA inhibition a step forward in the fight against pathogens?
These characteristics make HtrA a potentially attractive candidate for novel therapeutic approaches to treat bacterial pathogenesis.
In contrast to other investigated bacterial species, H. pylori HtrA synthesis appears to be crucially important for bacterial physiology and survival since any intervention via mutagenesis or deletion of the htrA gene in the genome of H. pylori has not been successful up to date [20, 40, 41]. Correspondingly, a naturally occurring htrA-negative H. pylori isolate was not found in a comprehensive screening of more than 990 samples . These observations point to the question whether pharmacological inhibition of HtrA could tackle H. pylori physiology specifically? Helicobacter HtrA inhibitor (HHI) was the first described small molecule compound inhibiting H. pylori HtrA , which blocked HtrA-mediated E-cadherin cleavage and subsequent bacterial transmigration across a polarized epithelial monolayer. However, HHI did not affect the bacterial survival  and it is unknown, whether HHI is actually taken up by the bacteria. A first step in the direction of a future targeted H. pylori therapy has recently been made by demonstrating that compound 1 drastically affected H. pylori survival and/or growth [41, 62]. The data obtained suggest that compound 1 penetrates the bacterial cell wall to block periplasmic HtrA activity and subsequently H. pylori survival. Further research will be necessary to identify and optimize small molecule HtrA inhibitors as anti-H. pylori pharmacological lead compounds.
New strategies are urgently needed to combat bacterial infections. At the first glance, targeting a widespread bacterial enzyme does not appear to be straightforward. However, considering the HtrA-mediated host cell factor processing as a central step in the pathogenesis of many different infectious bacteria opens up a new perspective. Inhibiting extracellular HtrA by compounds that do not penetrate the bacterial membrane will likely not affect the colonization and survival of commensals; thus solely interference of pathogens with their individual virulence/pathogenic factors with the epithelium will be limited. Potent HtrA inhibitors penetrating the periplasm of H. pylori might pave the way towards a targeted anti-H. pylori treatment owed to the fact that H. pylori physiology essentially requires functional HtrA activity. While many of the current antibiotics affect all bacteria independently of assets and drawbacks for the colonized host, pathogen-selective HtrA inhibitors might present a drug discovery opportunity.
Periplasmic serine endoproteases
High temperature requirement A
Postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (ZO-1).
The work of S.W. was supported by the grants P_24074 and W_1213 from the Austrian Science Fund (FWF). The work of G.S. was supported by the OPO-Foundation Zurich. The work of S.B. was supported by the Deutsche Forschungsgemeinschaft (B10 in CRC-796 and A04 in CRC-1181).
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and its additional files.
Wrote the paper: SW, GS, SB. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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