N-Aryl-3-mercaptosuccinimides as Antivirulence Agents Targeting Pseudomonas aeruginosa Elastase and Clostridium Collagenases.

Jelena Konstantinović,Anna K H Hirsch,Jörg Haupenthal,Hans Brandstetter,Samir Yahiaoui,Rolf W Hartmann,Esther Schönauer,Anastasia Andreas,Fabian K Berger,Rolf Müller,Markus Bischoff,Jesko Koehnke,Andreas M Kany,Alaa Alhayek

doi:10.1021/acs.jmedchem.0c00584

Abstract

In light of the global antimicrobial-resistance crisis, there is an urgent need for novel bacterial targets and antibiotics with novel modes of action. It has been shown that Pseudomonas aeruginosa elastase (LasB) and Clostridium histolyticum (Hathewaya histolytica) collagenase (ColH) play a significant role in the infection process and thereby represent promising antivirulence targets. Here, we report novel N-aryl-3-mercaptosuccinimide inhibitors that target both LasB and ColH, displaying potent activities in vitro and high selectivity for the bacterial over human metalloproteases. Additionally, the inhibitors demonstrate no signs of cytotoxicity against selected human cell lines and in a zebrafish embryo toxicity model. Furthermore, the most active ColH inhibitor shows a significant reduction of collagen degradation in an ex vivo pig-skin model.

Highlights

The growing number of antibiotic-resistant bacteria represents one of the biggest risks to public health, leading to an increasing number of infections that are difficult to treat
Clostridiaceae represent a family of Gram-positive bacteria that are known as causative agents of numerous fatal diseases with high mortality rates worldwide, such as botulism (Clostridium botulinum), soft-tissue infections like gas gangrene and wound infections (Clostridium perfringens, Clostridium histolyticum) and tetanus (Clostridium tetani).[11,12]
Collagenases cause tissue destruction via collagen degradation, which plays a significant role in the infection process by allowing the bacteria to reach anaerobic sites in host tissue and spread the infection.[15,16]

Summary

Introduction

The growing number of antibiotic-resistant bacteria represents one of the biggest risks to public health, leading to an increasing number of infections that are difficult to treat. Collagenases cause tissue destruction via collagen degradation, which plays a significant role in the infection process by allowing the bacteria to reach anaerobic sites in host tissue and spread the infection.[15,16] This especially affects the wound infection prognosis and results in a delayed healing process.[17,18]

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Methods

Results

Conclusion