Antimicrobial drugs that target human – not microbial – genotypes or phenotypes: A paradigm change in human evolutionary response to pathogen selection pressure

Apte, Sanjana; Apte, Paul

doi:10.1016/j.mehy.2006.01.043

Cited by 1 publication

(1 citation statement)

References 24 publications

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“…Therefore, the generation of new anti-infective agents has emerged as an unmet need in the therapeutics of microbial infection including neonatal bacteremia and meningitis. Host-directed therapeutics against pathogens may provide more effective approaches to perturbing host pathways used by pathogens in various stages of their life cycle, namely, adhesion, invasion, and growth [ 15 , 16 ]. Bacterial meningitis exhibits triad hallmark features (THFs): NFκB activation, pathogen penetration and leukocyte transmigration across the blood-brain barrier (BBB), which consists mainly of brain microvascular endothelial cells (BMEC) [ 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

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

Bao

Peng

et al. 2015

PLoS ONE

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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.

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