The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that can be very hard to treat because of high resistance to different antibiotics and alternative treatment regimens are greatly needed. An alternative or a complement to traditional antibiotic is to inhibit virulence of the bacteria. The salicylidene acylhydrazide, INP0341, belongs to a class of compounds that has previously been shown to inhibit virulence in a number of Gram-negative bacteria. In this study, the virulence blocking effect of INP0341 on P. aeruginosa was studied in vitro and in vivo. Two important and closely related virulence system were examined, the type III secretion system (T3SS) that translocates virulence effectors into the cytosol of the host cell to evade immune defense and facilitate colonization and the flagella system, needed for motility and biofilm formation. INP0341 was shown to inhibit expression and secretion of the T3SS toxin exoenzyme S (ExoS) and to prevent bacterial motility on agar plates and biofilm formation. In addition, INP0341 showed an increased survival of P. aeruginosa-infected mice. In conclusion, INP0341 attenuates P. aeruginosa virulence.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…[222][223][224] Salicylidene acylhydrazides (SAHs) represent aw ell-known class of T3SS inhibitors that have been extensively studied in various pathogens including P. aeruginosa and Salmonella typhimurium. [225][226][227][228][229] However, these SAHs seem to function through several mechanisms which need further elucidation. [225][226][227][228][229] However, these SAHs seem to function through several mechanisms which need further elucidation.…”

“…[224] Diverse SAH derivatives such as INP0341 have been synthesized and were found to attenuate bacterial pathogenesis. [225][226][227][228][229] However, these SAHs seem to function through several mechanisms which need further elucidation. [230] In ad ifferent approach, screening of compound libraries with acellular reporter assay revealed phenoxyacetamide MBX 1641 to be ap otent inhibitor of P. aeruginosa T3SS (IC 50 % 10 mm)w ith al ow toxicity against eukaryotic cells ( Figure 16).…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…[221] Es wurde eine Reihe von T3SS-Inhibitoren entdeckt, welche die Regulation der Expression des T3SS,d ie Synthese der nadelartigen Struktur sowie die Sekretion und Tr anslokation von Effektorproteinen beeinflussen (Abbildung 16). [225][226][227][228][229] Diese SAHs scheinen über verschiedene Mechanismen zu wirken, welche noch genauer aufgeklärt werden müssen. [224] Vielfältige SAH-Derivate,wie INP0341, wurden synthetisiert und führten zu einer Verringerung der bakteriellen Pathogenität.…”

“…[224] Vielfältige SAH-Derivate,wie INP0341, wurden synthetisiert und führten zu einer Verringerung der bakteriellen Pathogenität. [225][226][227][228][229] Diese SAHs scheinen über verschiedene Mechanismen zu wirken, welche noch genauer aufgeklärt werden müssen. [230] In einem weiteren Ansatz konnte durch ein Screening von Substanzbibliotheken in einem zellulären Reporter-Assay das Phenoxyacetamid MBX 1641 als wirksamer Inhibitor gegen das T3SS in P. aeruginosa (IC 50 % 10 mm)i dentifiziert werden (Abbildung 16).…”

Exploring resveratrol dimers as virulence blocking agents – Attenuation of type III secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa

“…Antibodies binding to proteins at the tip of the needle structure block T3SS function and promote passive protection in animal infection models 1 . In addition, mutation of the T3SS reduces infection of eukaryotic cells and mice 2,3 . The T3SS is conserved among a large number of Gram-negative pathogens and research over the last decades has demonstrated that the T3SS constitutes a validated target for the development of novel pathogen selective therapeutic agents 4 .…”