Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine‐gingipain inhibitor COR388

Abstract

COR388, a small‐molecule lysine‐gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine‐gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28‐day dose‐response study, COR388 inhibited the lysine‐gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine‐gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine‐gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine‐gingipain and eliminating P. gingivalis infection in humans.

The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease

“…Furthermore, incubating P. gingivalis with Aβ 1–42 peptides led to a significant increase in P. gingivalis death. These two findings further support the antimicrobial hypothesis for Aβ peptides [ 153 ]. Gingipain inhibitors, such as COR286, COR271 and COR388, have been found to be effective in inducing P. gingivalis death and reducing the bacterial load in the brain, more so than other antibiotics, such as moxifloxacin [ 153 , 154 ].…”

“…These two findings further support the antimicrobial hypothesis for Aβ peptides [ 153 ]. Gingipain inhibitors, such as COR286, COR271 and COR388, have been found to be effective in inducing P. gingivalis death and reducing the bacterial load in the brain, more so than other antibiotics, such as moxifloxacin [ 153 , 154 ]. In addition, COR271 was found to provide some level of neuroprotection as well [ 153 ].…”

“…Gingipain inhibitors, such as COR286, COR271 and COR388, have been found to be effective in inducing P. gingivalis death and reducing the bacterial load in the brain, more so than other antibiotics, such as moxifloxacin [ 153 , 154 ]. In addition, COR271 was found to provide some level of neuroprotection as well [ 153 ]. The administration of gingipain inhibitors has also been associated with a decrease in host Aβ 1–42 response to P. gingivalis infection [ 68 ].…”

Cognitive Decline and Oral Microbiota. Pro-Inflammatory Conditions Become Risk Factors in Neurodegenerative Disease

“…There is an increased risk of tooth decay, mucositis, dysgeusia and alterations of the oral microbiome [7]. showing that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of Pg in humans [8].…”

Porphyromonas spp. have an extensive host range in ill and healthy individuals and an unexpected environmental distribution: A systematic review and meta-analysis

“…As such, P. gingivalis and P. gulae appear as two ecotypes separated according to number of human and canine cases [110,111] and distinguishable by the catalase test, P. gulae being positive and P. gingivalis negative [35]. Nevertheless, these two species contain similar virulence factors [85,112]. P. gulae can invade human cells in vitro [113] but with less adherence to human cells than P. gingivalis [114].…”