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.
Highlights
The most common newborn deaths worldwide are neonatal infections, which currently cause about 1.6 million deaths annually in developing countries [1]
Using the in vitro (BMEC) and in vivo models of the blood-brain barrier (BBB), we present novel findings that provide proof of principle of the feasibility of treating meningitic E. coli K1 infection by targeting the host receptor α7 nAChR that is an essential regulator of inflammation manipulated by bacterial pathogens
Our findings show that the FDA-approved drug MEM is a potent inhibitor of the intracellular survival of meningitic E. coli K1 in brain microvascular endothelial cells (BMEC)
Summary
The most common newborn deaths worldwide are neonatal infections, which currently cause about 1.6 million deaths annually in developing countries [1]. One of the major infectious problems in the neonatal intensive care unit is neonatal bacteremia or sepsis, which is essential for the development of bacterial meningitis [2] This disease is associated with high mortality rates, increased medical costs and potentially poor long-term neurological sequelae [2,3,4,5]. Intrapartum prophylaxis (IP) of GBS carriers and selective administration of antibiotics to neonates greatly reduce newborn GBS infection [6,7,8] This has led to a major concern about whether IP use of antibiotics affects the incidence and the resistance of early-onset neonatal infection with nonGBS pathogens [6]. The ongoing antimicrobial resistance crisis will be certainly enhanced by WAU, leading to the increasing global incidence of infectious diseases to which we have no known reliable antimicrobial agent [12]
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