Dataset Information

Second Generation of Zafirlukast Derivatives with Improved Activity against the Oral Pathogen Porphyromonas gingivalis.

ABSTRACT: Porphyromonas gingivalis is a Gram-negative anaerobic pathogen that can trigger oral dysbiosis as an early event in the pathogenesis of periodontal disease. The FDA-approved drug zafirlukast (ZAF) was recently shown to display antibacterial activity against P. gingivalis. Here, 15 novel ZAF derivatives were synthesized and evaluated for their antibacterial activity against P. gingivalis and for their cytotoxic effects. Most derivatives displayed superior antibacterial activity against P. gingivalis compared to ZAF and its first generation derivatives along with little to no growth inhibition of other oral bacterial species. The most active compounds displayed bactericidal activity against P. gingivalis and less cytotoxicity than ZAF. The superior and selective antibacterial activity of ZAF derivatives against P. gingivalis along with an increased safety profile compared to ZAF suggest these new compounds, especially 14b and 14e, show promise as antibacterials for future studies aimed to test their potential for preventing/treating P. gingivalis-induced periodontal disease.

SUBMITTER: Howard KC

PROVIDER: S-EPMC7549265 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Second Generation of Zafirlukast Derivatives with Improved Activity against the Oral Pathogen Porphyromonas gingivalis.

Howard Kaitlind C KC Gonzalez Octavio A OA Garneau-Tsodikova Sylvie S

ACS medicinal chemistry letters 20200318 10

Porphyromonas gingivalis is a Gram-negative anaerobic pathogen that can trigger oral dysbiosis as an early event in the pathogenesis of periodontal disease. The FDA-approved drug zafirlukast (ZAF) was recently shown to display antibacterial activity against P. gingivalis. Here, 15 novel ZAF derivatives were synthesized and evaluated for their antibacterial activity against P. gingivalis and for their cytotoxic effects. Most derivatives displayed superior antibacterial activi ...[more]

PMID: 33062172

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Project description:BackgroundPorphyromonas gingivalis (hereafter "Pg") is an oral pathogen that has been hypothesized to act as a keystone driver of inflammation and periodontal disease. Although Pg is most readily recovered from individuals with actively progressing periodontal disease, healthy individuals and those with stable non-progressing disease are also colonized by Pg. Insights into the factors shaping the striking strain-level variation in Pg, and its variable associations with disease, are needed to achieve a more mechanistic understanding of periodontal disease and its progression. One of the key forces often shaping strain-level diversity in microbial communities is infection of bacteria by their viral (phage) predators and symbionts. Surprisingly, although Pg has been the subject of study for over 40 years, essentially nothing is known of its phages, and the prevailing paradigm is that phages are not important in the ecology of Pg.ResultsHere we systematically addressed the question of whether Pg are infected by phages-and we found that they are. We found that prophages are common in Pg, they are genomically diverse, and they encode genes that have the potential to alter Pg physiology and interactions. We found that phages represent unrecognized targets of the prevalent CRISPR-Cas defense systems in Pg, and that Pg strains encode numerous additional mechanistically diverse candidate anti-phage defense systems. We also found that phages and candidate anti-phage defense system elements together are major contributors to strain-level diversity and the species pangenome of this oral pathogen. Finally, we demonstrate that prophages harbored by a model Pg strain are active in culture, producing extracellular viral particles in broth cultures.ConclusionThis work definitively establishes that phages are a major unrecognized force shaping the ecology and intra-species strain-level diversity of the well-studied oral pathogen Pg. The foundational phage sequence datasets and model systems that we establish here add to the rich context of all that is already known about Pg, and point to numerous avenues of future inquiry that promise to shed new light on fundamental features of phage impacts on human health and disease broadly. Video Abstract.

Dataset Information

Second Generation of Zafirlukast Derivatives with Improved Activity against the Oral Pathogen Porphyromonas gingivalis.

Publications

Second Generation of Zafirlukast Derivatives with Improved Activity against the Oral Pathogen <i>Porphyromonas gingivalis</i>.

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