Abstract
Periodontitis is a severe yet underestimated oral disease. Since it is linked to several systemic diseases, such as diabetes, artheriosclerosis, and even Alzheimer’s disease, growing interest in treating periodontitis has emerged recently. The major cause of periodontitis is a shift in the oral microbiome. A keystone pathogen that is associated with this shift is Porphyromonas gingivalis. Hence, targeting P. gingivalis came into focus of drug discovery for the development of novel antiinfective compounds. Among others, glutaminyl cyclases (QCs) of oral pathogens might be promising drug targets. Here, we report the discovery and structure–activity relationship of a novel class of P. gingivalis QC inhibitors according to a tetrahydroimidazo[4,5-c]pyridine scaffold. Some compounds exhibited activity in the lower nanomolar range and thus were further characterized with regard to their selectivity and toxicity.
Highlights
One of the most diverse microbiomes is found in the human oral cavity, where more than 700 different bacteria species have been identified [1,2]
Fungi, viruses, and protozoa, the “healthy” ecosystem, which is essential for maintaining both oral and systemic health. Disruption of this homeostasis, e.g., by lack of oral hygiene, genetic predisposition, tobacco and alcohol consumption, stress, aging, and immune disorders, can be the initial step for the development and progression of oral disease such as periodontitis, which is often accompanied by overgrowth of certain bacteria
Bacterial type II glutaminyl cyclases recently emerged as potential drug targets for selectively combating the bacteria responsible for the development of periodontitis
Summary
One of the most diverse microbiomes is found in the human oral cavity, where more than 700 different bacteria species have been identified [1,2]. Periodontitis is a microbial-shift disease, where pathogenic bacteria become predominant and build up a polymicrobial dysbiotic community This leads to degradation of tooth-supporting structures and, if not treated, subsequently to bone loss. P. gingivalis is considered to be a keystone of periodontitis that supports biofilm Another treatment strategy couldpathogen target P. gingivalis throughthe an growth of further pathogens and the shift of the oral microbiome towards a pathogenic inhibition of a physiological essential enzymes, e.g., glutaminyl cyclase (PgQC), by small biofilm. Another treatment strategy could target through an molecules. Has been classified as an “essential” gene by transposon-mutagenesis experiments [26,27]
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