Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

Abstract

Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer’s disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial infection through modulation of both inflammatory and anti-inflammatory pathways.

Pathogenic Triad in Bacterial Meningitis: Pathogen Invasion, NF-κB Activation, and Leukocyte Transmigration that Occur at the Blood-Brain Barrier

“…It is also a transcriptional activator of many genes involved in the pathogenic triad of BM (e.g., IL–1β, TNF–α, IL-6, IL-8). During the past several decades, evidence has accumulated that deregulated activity of this pathway has been linked to the progression of a number of human diseases, including cancer, BM, rheumatoid arthritis, streptococcal cell wall-induced arthritis, experimental colitis, septic shock, Alzheimer's disease, multiple sclerosis, traumatic CNS injury, and cerebral ischemia (Koedel et al, 2000 ; de Souza et al, 2011 ; Anthony Jalin et al, 2015 ; Bennani-Baiti et al, 2015 ; Yu et al, 2015 ). Therefore, the NF-kB signaling pathway should be a good drug target that can hasten development of novel therapeutic agents.…”

Memantine Displays Antimicrobial Activity by Enhancing Escherichia coli Pathogen-Induced Formation of Neutrophil Extracellular Traps

“…Our laboratory has demonstrated that α7R is an essential regulator of the host inflammatory response against bacteria (Chi et al, 2011). α7R-mediated inflammatory effects could be blocked by its antagonist, MEM (Yu et al, 2015). Based on these findings, we hypothesized that MEM interacts first with the drug target α7R and then induce NET-mediated bacterial killing in PMNs.…”

“…These bacteria infect at least 2 million people per year in the USA alone, with 23,000 dying as a direct result of these infections (Khan and Siddiqui, 2014). It suggests that there is an emergent need to develop new antibacterial drugs with novel strategies (Yu et al, 2015).…”

“…Development of a serious bacterial infection basically represents a failure of innate immune cells to execute their antimicrobial defense function (Munguia and Nizet, 2017). Pharmacologically targeting powerful immune cell killing and boosting the host defense system against pathogens could be an important way to treat infections, and would reduce frequencies in inducing drug resistance (Yu et al, 2015;Munguia and Nizet, 2017;Chiang et al, 2018).…”

“…target for broad-spectrum host-directed antimicrobial agents against bacterial infections, which lead to bacteremia and all too often sepsis. Using in vitro and in vivo models of the BBB and RNA-seq (Yu et al, 2015), our drug repositioning studies have shown that memantine (MEM), an FDA-approved drug for the treatment of Alzheimer's disease (AD), efficiently blocks pathogenicities induced by meningitic Escherichia coli E44 and IHE2015 (a multiple antibiotic-resistant strain) in a manner dependent on α7R. In addition, we found that MEM efficiently inhibits bacteremia caused by E. coli in an animal model (Wang et al, 2015;Yu et al, 2015).…”