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Group B Streptococcus (GBS) is an encapsulated gram-positive bacterial pathogen which causes severe perinatal infections. Human milk oligosaccharides (HMOs) are short-chain sugars that have recently been shown to possess antimicrobial and anti-biofilm activity against a variety of bacterial pathogens, including GBS. We have expanded these studies to demonstrate that HMOs can inhibit and dismantle biofilm in both invasive and colonizing strains of GBS. A cohort of 30 diverse strains of GBS were analyzed for susceptibility to HMO-dependent biofilm inhibition or destruction. HMOs were significantly effective at inhibiting biofilm in capsular type and sequence type specific fashion, with significant efficacy in CpsIb, CpsII, CpsIII, CpsV, and CpsVI strains as well as ST-1, ST-12, ST-19, and ST-23 strains. Interestingly, CpsIa as well as ST-7 and ST-17 were not susceptible to the anti-biofilm activity of HMOs, underscoring the strain-specific effects of these important antimicrobial molecules against the perinatal pathogen, S. agalactiae.

Streptococcus agalactiae, also known as group B Streptococcus (GBS), is a Gram-positive encapsulated bacterium that colonizes the gastrointestinal tract of 30 to 50% of humans. GBS causes invasive infection during pregnancy that can lead to chorioamnionitis, funisitis, preterm prelabor rupture of membranes (PPROM), preterm birth, neonatal sepsis, and maternal and fetal demise. Upon infecting the host, GBS encounters sentinel innate immune cells, such as macrophages, within reproductive tissues. Once phagocytosed by macrophages, GBS upregulates the expression of the gene

Background & Aims Intestinal mucositis, a severe complication of antineoplastic therapeutics, is characterized by mucosal injury and inflammation in the small intestine. Therapies for the prevention and treatment of this disease are needed. We investigated whether 2’-fucosyllactose (2’-FL), an abundant oligosaccharide in human milk, protects intestinal integrity and ameliorates intestinal mucositis. Methods A mouse small intestinal epithelial (MSIE) cell line, mouse enteroid cultures, and human gastrointestinal tumor cell lines (AGS and HT29) were co-treated with the chemotherapy agent 5-fluorouracil (5-FU) and 2’-FL. Mice were injected intraperitoneally with 5-FU to induce intestinal mucositis. 2’-FL was administered in the drinking water to mice before (pretreatment) or concurrently with 5-FU injection. Body weight and pathologic changes were analyzed. Results 2’-FL alleviated 5-FU inhibition of cell growth in MSIE cells, but not in AGS and HT29 cells. The 5-FU–induced apoptosis in MSIE cells and enteroids was suppressed by 2’-FL. Compared with 5-FU treatment alone, 2’-FL pretreatment protected against body weight loss, and ameliorated inflammation scores, proinflammatory cytokine production, shortening of villi, epithelial cell apoptosis, goblet cell loss, and tight junctional complex disruption in the small intestine. 2’-FL concurrent treatment had less of an effect on intestinal mucositis than 2’-FL pretreatment. Interestingly, no effect of 2’-FL was observed on 5-FU–induced S-phase arrest in MSIE, AGS, and HT29 cells. Neither pretreatment nor concurrent treatment with 2’-FL affected 5-FU–induced inhibition of proliferation in MSIE cells. Conclusions This study shows a novel direct effect of 2’-FL in protecting small intestinal epithelial cells against apoptosis stimulated by 5-FU, which may contribute to prevention of 5-FU–induced intestinal mucositis., Graphical abstract

Streptococcus agalactiae, also known as Group BStreptococcus(GBS), is a Gram- positive encapsulated bacterium that colonizes the gastrointestinal tract of 30-50% of humans. GBS causes invasive infection during pregnancy that can lead to chorioamnionitis, funisitis, preterm prelabor rupture of membranes (PPROM), preterm birth, neonatal sepsis, and maternal and fetal demise. Upon infecting the host, GBS encounters sentinel innate immune cells, such as macrophages, within reproductive tissues. Once phagocytosed by macrophages, GBS upregulates expression of the gene,npx, which encodes a NADH peroxidase. GBS mutants with anpxdeletion (Δnpx) are exquisitely sensitive to reactive oxygen stress. Furthermore, we have shown thatnpxis required for GBS survival in both THP-1 and placental macrophages. In anin vivomurine model of ascending GBS vaginal infection during pregnancy,npxis required for invasion of reproductive tissues and is critical for inducing disease progression including PPROM and preterm birth. Reproductive tissue cytokine production was also significantly diminished in Δnpxinfected animals compared to those infected with wild type (WT)-GBS. Complementationin transreversed this phenotype, indicatingnpxis critical for GBS survival and initiation of proinflammatory signaling in the gravid host.

Adverse pregnancy outcomes affect 54 million people globally per year, with at least 50% of these attributed to infection during gestation. These include inflammation of the membranes surrounding the growing fetus (chorioamnionitis), preterm prelabor rupture of membranes (PPROM), preterm birth (PTB), early-onset disease (EOD) and late-onset disease (LOD), neonatal and maternal sepsis, and maternal or fetal demise. Although universal screening and implementation of intrapartum antibiotic prophylaxis (IAP) has improved EOD outcomes, these interventions have not reduced the incidences of LOD or complications occurring early on during pregnancy such as PPROM and PTB. Thus, novel therapies are needed to prevent adverse pregnancy outcomes and to ameliorate disease risk in vulnerable populations. Lactoferrin has recently been explored as a potential therapeutic as it demonstrates strong antimicrobial and anti-biofilm activity. Lactoferrin is a glycoprotein capable of iron chelation found in a variety of human tissues and is produced in high concentrations in human breast milk. In recent studies, lactoferrin has shown promise inhibiting growth and biofilm formation of streptococcal species, including Group B Streptococcus (GBS), a prominent perinatal pathogen. Understanding the interactions between lactoferrin and GBS could elucidate a novel treatment strategy for adverse pregnancy outcomes caused by GBS infection.

Over the past century, human health has been enhanced by antimicrobial development. Following the deployment of the first antibiotics in the 1940s, bacterial resistance evolved and has increasingly outmaneuvered even the most promising antimicrobial agents. Accordingly, increased interest has been placed on alternative methods to circumvent antimicrobial resistance evolution. In the enclosed short review, we discuss the antimicrobial properties of human breast milk with a special emphasis on human milk oligosaccharides (HMOs). We recount studies across gram-negative and gram-positive pathogens, highlighting the usage of HMOs in promoting human health and wellness.

Zwitterionic carbohydrate modifications, such as phosphoethanolamine (PEtN), govern host-pathogen interactions. Whereas it is recognized that these modifications stimulate the host immune system, the purpose of PEtN modification remains largely descriptive. As an enabling step toward studying this carbohydrate modification, we report a synthesis of the P. temperata zwitterionic trisaccharide repeating unit. The 32-step synthesis was enabled by H-phosphonate chemistry to install the PEtN arm on a poorly reactive and sterically hindered C4-alcohol.

Few classes of natural products rival the structural audacity of oligosaccharides. Their complexity, however, has stood as an immense roadblock to translational research, as access to homogeneous material from nature is challenging. Thus, while carbohydrates are critical to the myriad functional and structural aspects of the biological sciences, their behavior is largely descriptive. This challenge presents an attractive opportunity for synthetic chemistry, particularly in the area of human milk science. First, there is an inordinate need for synthesizing homogeneous human milk oligosaccharides (HMOs). Superimposed on this goal is the mission of conducting syntheses at scale to enable animal studies. Herein, we present a personalized rumination of our involvement, and that of our colleagues, which has led to the synthesis and characterization of HMOs and mechanistic probes. Along the way, we highlight chemical, chemoenzymatic, and synthetic biology based approaches. We close with a discussion on emergent challenges and opportunities for synthesis, broadly defined, in human milk science.

Chronic infection with Helicobacter pylori increases risk of gastric diseases including gastric cancer. Despite development of a robust immune response, H. pylori persists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection with H. pylori strains which encode the cag Type IV Secretion System (cag T4SS). The cag T4SS is responsible for translocating the oncogenic protein CagA into host cells and inducing pro-inflammatory and carcinogenic signaling cascades. Our previous work demonstrated that nutrient iron modulates the activity of the T4SS and biogenesis of T4SS pili. In response to H. pylori infection, the host produces a variety of antimicrobial molecules, including the iron-binding glycoprotein, lactoferrin. Our work shows that apo-lactoferrin exerts antimicrobial activity against H. pylori under iron-limited conditions, while holo-lactoferrin enhances bacterial growth. Culturing H. pylori in the presence of holo-lactoferrin prior to co-culture with gastric epithelial cells, results in repression of the cag T4SS activity. Concomitantly, a decrease in biogenesis of cag T4SS pili at the host-pathogen interface was observed under these culture conditions by high-resolution electron microscopy analyses. Taken together, these results indicate that acquisition of alternate sources of nutrient iron plays a role in regulating the pro-inflammatory activity of a bacterial secretion system and present novel therapeutic targets for the treatment of H. pylori-related disease.

The synthesis of glycosides incorporating basic nitrogen atoms is a longstanding challenge in organic synthesis. By leveraging the reactivity of glycosyl anions, a general method has been developed that enables use of glycosyl donors incorporating unprotected, basic amines.

Acinetobacter baumannii is an opportunistic bacterial pathogen that causes severe infections in immunocompromised patients. The emergence of multi- and pan-drug resistant strains of A. baumannii from clinical sources has confounded treatment and enhanced morbidity and mortality associated with these infections. One way that A. baumannii circumnavigates environmental and antimicrobial challenge is by forming tertiary architectural structures of cells known as biofilms. Biofilm-inhibiting molecules could be deployed as a potential chemotherapeutic strategy to inhibit or disrupt A. baumannii biofilms and mitigate adverse outcomes due to infection. Lactoferrin is an innate immune glycoprotein produced in high concentrations in both human and bovine milk which has previously been shown to have antibacterial and antibiofilm activities. We sought to test lactoferrin against a bank of clinical isolates of A. baumannii to determine changes in bacterial growth or biofilm formation. Our results indicate that human lactoferrin has slightly more potent antibacterial activities than bovine lactoferrin against certain strains of A. baumannii and that these effects are associated with anatomical site of isolation. Additionally, we have shown that both bovine and human lactoferrin can inhibit A. baumannii biofilm formation and that these effects are associated with anatomical site of isolation and whether the strain forms robust or weak biofilms.

Streptococcus species are common causes of human infection. These Gram-positive, encapsulated bacterial pathogens infect diverse anatomic spaces, leading to infections including skin and soft tissue infection, endocarditis, pneumonia, meningitis, sinusitis, otitis media, chorioamnionitis, sepsis, and even death. Risk for streptococcal infection is highest in low- and middle-income countries where micronutrient deficiency is common. Epidemiological data reveal that vitamin D deficiency is associated with enhanced risk of streptococcal infection and cognate disease outcomes. Additionally, vitamin D improves antibacterial defenses by stimulating innate immune processes such as phagocytosis and enhancing production of reactive oxygen species (oxidative burst) and antimicrobial peptides (including cathelicidin and lactoferrin), which are important for efficient killing of bacteria. This review presents the most recent published work that studies interactions between the micronutrient vitamin D, the host immune system, and pathogenic streptococci as well as comparisons with other relevant infection models.

Alongside Edward, Lemieux was among the earliest researchers studying negative hyperconjugation (i.e. the anomeric effect) or the preference for gauche conformations about the C1-O5 bond in carbohydrates. Lemieux also studied an esoteric, if not controversial, theory known as the reverse anomeric effect (RAE). This theory is used to rationalize scenarios where predicted anomeric stabilization does not occur. One such example is the Kochetkov amination, where reducing end amines exist solely as the β-anomer. Herein, we provide a brief account of Lemieux’s contributions to the area of stereoelectronic effects and apply this knowledge toward the synthesis of β-amino human milk oligosaccharides (βA-HMOs). These molecules were evaluated for their ability to inhibit growth and biofilm production in Group B Streptococcus (GBS) and Staphylococcus aureus. While the parent HMOs lacked antimicrobial and antibiofilm activity, their β-amino derivatives significantly inhibit biofilm formation in both species. Field Emission Gun-Scanning Single Electron Microscopy (FEG-SEM) revealed that treatment of the β-amino HMOs significantly inhibits bacterial adherence and eliminates the ability of both microbes to form biofilms.

Streptococcal species are gram positive bacteria responsible for a variety of disease outcomes including pneumonia, meningitis, endocarditis, erysipelas, necrotizing fasciitis, periodontitis, skin and soft tissue infections, chorioamnionitis, premature rupture of membranes, preterm birth, and neonatal sepsis. In response to streptococcal infections, the host innate immune system deploys a repertoire of antimicrobial and immune modulating molecules. One important molecule that is produced in response to streptococcal infections is lactoferrin. Lactoferrin has antimicrobial properties including the ability to bind iron with high affinity and sequester this important nutrient from an invading pathogen. Additionally, lactoferrin has the capacity to alter the host inflammatory response and contribute to disease outcome. This review presents the most recent published work that studies the interaction between the host innate immune protein lactoferrin and the invading pathogen, Streptococcus.

The members of the infant microbiome are governed by feeding method (breastmilk vs. formula). Regardless of the source of nutrition, a competitive growth advantage can be provided to commensals through prebiotics - either human milk oligosaccharides (HMOs) or plant oligosaccharides that are supplemented into formula. To characterize how prebiotics modulate commensal - pathogen interactions, we have designed and studied a minimal microbiome where a pathogen, Streptococcus agalactiae engages with a commensal, Streptococcus salivarius. We discovered that while S. agalactiae suppresses the growth of S. salivarius via increased lactic acid production, galacto-oligosaccharides (GOS) supplementation reverses the effect. This result has major implications in characterizing how single species survive in the gut, what niche they occupy, and how they engage with other community members.

Acinetobacter baumannii is a serious threat to human health, per the Centers for Disease Control and Prevention’s latest threat assessment. A. baumannii is a gram-negative opportunistic bacterial pathogen that causes severe community and nosocomial infections in immunocompromised patients. Treatment of these infections is confounded by the emergence of multi- and pan-drug resistant strains of A. baumannii. A. baumannii colonizes abiotic and biotic surfaces and evades antimicrobial challenges by forming biofilms, which are three-dimensional architectural structures of cells adhered to a substrate and encased in an extracellular matrix comprised of polymeric substances such as polysaccharides, proteins, and DNA. Biofilm-inhibiting compounds have recently gained attention as a chemotherapeutic strategy to prevent or disperse A. baumannii biofilms and restore the utility of traditional antimicrobial strategies. Recent work indicates that human milk oligosaccharides (HMOs) have potent antibacterial and biofilm-inhibiting properties. We sought to test the utility of HMOs against a bank of clinical isolates of A. baumannii to ascertain changes in bacterial growth or biofilm formation. Our results indicate that out of 18 strains tested, 14 were susceptible to the anti-biofilm activities of HMOs, and that the potent anti-biofilm activity was observed in strains isolated from diverse anatomical sites, disease manifestations, and across antibiotic-resistant and susceptible strains.

Streptococcus agalactiae or Group B Streptococcus (GBS) is a Gram-positive bacterial pathobiont that is the etiological cause of severe perinatal infections. GBS can colonize the vagina of pregnant patients and invade tissues causing ascending infections of the gravid reproductive tract that lead to adverse outcomes including preterm birth, neonatal sepsis, and maternal or fetal demise. Additionally, transmission of GBS during labor or breastfeeding can also cause invasive infections of neonates and infants. However, human milk has also been shown to have protective effects against infection; a characteristic that is likely derived from antimicrobial and immunomodulatory properties of molecules that comprise human milk. Recent evidence suggests that human milk oligosaccharides (HMOs), short-chain sugars that comprise 8-20 % of breast milk, have antimicrobial and anti-biofilm activity against GBS and other bacterial pathogens. Additionally, HMOs have been shown to potentiate the activity of antibiotics against GBS. This review presents the most recent published work that studies the interaction between HMOs and GBS.

Perinatal infection with Streptococcus agalactiae, or Group B Streptococcus (GBS), is associated with preterm birth, neonatal sepsis, and stillbirth. Here, we study the interactions of GBS with macrophages, essential sentinel immune cells that defend the gravid reproductive tract. Transcriptional analyses of GBS-macrophage co-cultures reveal enhanced expression of a gene encoding a putative metal resistance determinant, cadD. Deletion of cadD reduces GBS survival in macrophages, metal efflux, and resistance to metal toxicity. In a mouse model of ascending infection during pregnancy, the ΔcadD strain displays attenuated bacterial burden, inflammation, and cytokine production in gestational tissues. Furthermore, depletion of host macrophages alters cytokine expression and decreases GBS invasion in a cadD-dependent fashion. Our results indicate that GBS cadD plays an important role in metal detoxification, which promotes immune evasion and bacterial proliferation in the pregnant host.

Acinetobacter baumannii is an opportunistic bacterial pathogen that causes severe infections in immunocompromised patients. The emergence of multi- and pan-drug resistant strains of A. baumannii from clinical sources has confounded treatment and enhanced morbidity and mortality associated with these infections. One way that A. baumannii circumnavigates environmental and antimicrobial challenge is by forming tertiary architectural structures of cells known as biofilms. Biofilm-inhibiting molecules could be deployed as a potential chemotherapeutic strategy to inhibit or disrupt A. baumannii biofilms and mitigate adverse outcomes due to infection. Lactoferrin is an innate immune glycoprotein produced in high concentrations in both human and bovine milk which has previously been shown to have antibacterial and anti-biofilm activities. We sought to test lactoferrin against a bank of clinical isolates of A. baumannii to determine changes in bacterial growth or biofilm formation. Our results indicate that human lactoferrin has slightly more potent antibacterial activities than bovine lactoferrin against certain strains of A. baumannii and that these effects are associated with anatomical site of isolation. Additionally, we have shown that both bovine and human lactoferrin can inhibit A. baumannii biofilm formation and that these effects are associated with anatomical site of isolation and whether the strain forms robust or weak biofilms.

Group B Streptococcus (GBS) is an encapsulated Gram-positive pathogen that causes ascending infections of the reproductive tract during pregnancy. The capsule of this organism is a critical virulence factor that has been implicated in a variety of cellular processes to promote pathogenesis. Primarily comprised of carbohydrates, the GBS capsule, and its synthesis is driven by the capsule polysaccharide synthesis (cps) operon. The cpsE gene within this operon encodes a putative glycosyltransferase that is responsible for the transfer of a Glc-1-P from UDP-Glc to an undecaprenyl lipid molecule. We hypothesized that the cpsE gene product is important for GBS virulence and ascending infection during pregnancy. Our work demonstrates that a GBS cpsE mutant secretes less carbohydrates, has reduced capsule, and forms less biofilm than the wild-type parental strain. We show that compared to the parental strain, the ΔcpsE deletion mutant is more readily taken up by human placental macrophages and has significantly attenuated ability to invade and proliferate in the mouse reproductive tract. Taken together, these results demonstrate that the cpsE gene product is an important virulence factor that aids in GBS colonization and invasion of the gravid reproductive tract.

Urinary tract infections (UTIs) are caused by bacteria growing in complex, multicellular enclosed aggregates known as biofilms. Recently, a zwitterionic cellulose derivative produced in Escherichia coli (E. coli) was determined to play an important role in the formation and assembly of bacterial biofilms. In order to produce a minimal, yet structurally defined tool compound to probe the biology of the naturally occurring polymer, we have synthesized a zwitterionic phosphoethanolamine cellobiose (pEtN cellobiose) and evaluated its biofilm activity in the gram-negative bacterium E. coli, a pathogen implicated in the pathogenesis of UTIs. The impact of synthetic pEtN cellobiose on bacterial biofilm formation was examined via colorimetric assays which revealed an increase in cellular adhesion to an abiotic substrate compared to untreated samples. Additionally, Congo red binding assays indicate that culturing E. coli in the presence of pEtN cellobiose enhances Congo red binding to bacterial cells. These results reveal new opportunities to study the impact glycopolymers have on cellular adhesion in gram-negative pathogens.

Staying balanced: In this Science Voices article, Prof. Steven Townsend addresses strategies for obtaining a healthy start in academic careers and the provides a personal insight on assessing priorities and obtaining work-life integration as an independent researcher.

Zwitterionic polysaccharides (ZPSs) activate T-cell-dependent immune responses by major histocompatibility complex class II presentation. Herein, we report the first synthesis of a Morganella morganii ZPS repeating unit as an enabling tool in the synthesis of novel ZPS materials. The repeating unit incorporates a 1,2-cis-α-glycosidic bond; the problematic 1,2-trans-galactosidic bond, Gal-β-(1 → 3)-GalNAc; and phosphoglycerol and phosphocholine residues which have not been previously observed together as functional groups on the same oligosaccharide. The successful third-generation approach leverages a first in class glycosylation of a phosphoglycerol-functionalized acceptor. To install the phosphocholine unit, a highly effective phosphocholine donor was synthesized.

2'-Fucosyllactose (2'-FL) is a ubiquitous oligosaccharide in human milk. Importantly, this carbohydrate promotes the growth of several strains of Bifidobacteria, a class of beneficial gut commensal, and inhibits epithelial binding of pathogens. In light of these protective effects, we elected to evaluate the potential of 2'-FL to serve as an antibacterial agent against Group B Streptococcus (GBS). While 2'-FL was devoid of any substantial antimicrobial or antibiofilm activity, conversion of 2'-FL to its reducing end β-amine provided a novel antibiofilm compound.

Staphylococcus aureus (S. aureus) is an asymptomatic colonizer of 30% of all human beings. While generally benign, antibiotic resistance contributes to the success of S. aureus as a human pathogen. Resistance is rapidly evolved through a wide portfolio of mechanisms including horizontal gene transfer and chromosomal mutation. In addition to traditional resistance mechanisms, a special feature of S. aureus pathogenesis is its ability to survive on both biotic and abiotic surfaces in the biofilm state. Due to this characteristic, S. aureus is a leading cause of human infection. Methicillin-resistant S. aureus (MRSA) in particular has emerged as a widespread cause of both community- and hospital-acquired infections. Currently, MRSA is responsible for 10-fold more infections than all multi-drug resistant (MDR) Gram-negative pathogens combined. Recently, MRSA was classified by the World Health Organization (WHO) as one of twelve priority pathogens that threaten human health. In this targeted mini-review, we discuss MRSA biofilm production, the relationship of biofilm production to antibiotic resistance, and front-line techniques to defeat the biofilm-resistance system.

Group B Streptococcus (GBS) is an encapsulated gram-positive human pathogen which causes invasive infections in pregnant hosts and neonates, as well as immunocompromised individuals. Colonization of the human host requires the ability to adhere to mucosal surfaces and circumnavigate the nutritional challenges and antimicrobial onslaught associated with the innate immune response. Biofilm formation is a critical process to facilitate GBS survival and establishment of a replicative niche in the vertebrate host. Previous work has shown that the host responds to GBS infection by producing the innate antimicrobial glycoprotein lactoferrin, which has been implicated in repressing bacterial growth and biofilm formation. Additionally, lactoferrin is highly abundant in human breast milk and could serve a protective role against invasive microbial pathogens. Our work demonstrates that human breast milk lactoferrin has antimicrobial and anti-biofilm activity against GBS and inhibits GBS adherence to human gestational membranes. Together these results indicate that human milk lactoferrin could be utilized as a prebiotic chemotherapeutic strategy to limit the impact of bacterial adherence and biofilm formation on GBS-associated disease outcomes.

In addition to providing maximal nutritional value for neonatal growth and development, human milk functions as an early defense mechanism against invading pathogens. Human milk oligosaccharides (HMOs), which are abundant in human milk, are a diverse group of heterogeneous carbohydrates with wide ranging protective effects. In addition to promoting the colonization of beneficial intestinal flora, HMOs serve as decoy receptors, effectively blocking the attachment of pathogenic bacteria and viruses. HMOs also function as bacteriostatic agents, inhibiting the growth of gram-positive bacteria. Based on this precedence, an emerging area in the field has focused on characterizing the antiviral properties of HMOs. Indeed, HMOs have been evaluated for their potential as antiviral agents, with many shown to possess activity against life-threatening infections. This targeted review provides insight to the known glycan-binding interactions between select HMOs and influenza, rotavirus, respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), and norovirus. Additionally, we review the role of HMOs in preventing necrotizing enterocolitis (NEC), an intestinal disease linked to viral infections. We close with a discussion of what is known, broadly regarding human milk oligosaccharides and their interactions with coronaviruses.

Presented herein is the synthesis of the Aeromonas veronii disaccharide repeating unit which has been achieved in 11 steps starting from d-fucose and d-galactosamine.

Purpose Maternal obesity, affecting nearly 1 in 4 pregnancies, is associated with increased circulating saturated fatty acids, such as palmitate. These fatty acids are implicated in placental inflammation, which may in turn exacerbate both maternal–fetal tolerance and responses to pathogens, such as group B Streptococcus. In this review, we address the question, “How do obesity and associated fatty acids influence placental inflammation?” Methods In this narrative review, we searched PubMed and Google Scholar using combinations of the key words placental inflammation or pregnancy and lipids, fatty acids, obesity, palmitate, or other closely related search terms. We also used references found within these articles that may have been absent from our original search queries. We analyzed methods and key results of these articles to compare and contrast their findings, which were occasionally at odds with each other. Findings Although obesity can be studied as a whole, complex phenomena with in vivo mouse models and human samples from patients with obesity, in vitro modeling often relies on the treatment of cells or tissues with ≥1 fatty acids and occasionally other compounds (eg, glucose and insulin). We found that palmitate, most commonly used in vitro to recreate hallmarks of obesity, induces apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation in many placental cell types. We compare this to in vivo models of obesity wherever possible. We found that obesity as a whole may have more complex regulation of these phenomena (apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation) compared with in vitro models of fatty acid treatment (primarily palmitate) because of the presence of unsaturated fatty acids (ie, oleate), which may have anti-inflammatory effects. Implications The interaction of unsaturated fatty acids with saturated fatty acids may ameliorate many inflammatory effects of saturated fatty acids alone, which complicates interpretation of in vitro studies that focus on a particular fatty acid in isolation. This complication may explain why certain studies of obesity in vivo have differing outcomes from studies of specific fatty acids in vitro.

Starting shortly after parturition, and continuing throughout our lifetime, the gut microbiota coevolves with our metabolic and neurological programming. This symbiosis is regulated by a complex interplay between the host and environmental factors, including diet and lifestyle. Not surprisingly, the development of this microbial community is of critical importance to health and wellness. In this targeted review, we examine the gut microbiome from birth to 2 years of age to characterize the role human milk oligosaccharides play in early formation of microbial flora.

Group B Streptococcus is an important human pathogen that causes serious infections during pregnancy which can lead to chorioamnionitis, funisitis, premature rupture of gestational membranes, preterm birth, neonatal sepsis, and death. GBS is evolving antimicrobial resistance mechanisms, and the work presented in this paper provides evidence that prebiotics such as human milk oligosaccharides can act as adjuvants to restore the utility of antibiotics., Adjuvants can be used to potentiate the function of antibiotics whose efficacy has been reduced by acquired or intrinsic resistance. In the present study, we discovered that human milk oligosaccharides (HMOs) sensitize strains of group B Streptococcus (GBS) to trimethoprim (TMP), an antibiotic to which GBS is intrinsically resistant. Reductions in the MIC of TMP reached as high as 512-fold across a diverse panel of isolates. To better understand HMOs’ mechanism of action, we characterized the metabolic response of GBS to HMO treatment using ultrahigh-performance liquid chromatography–high-resolution tandem mass spectrometry (UPLC-HRMS/MS) analysis. These data showed that when challenged by HMOs, GBS undergoes significant perturbations in metabolic pathways related to the biosynthesis and incorporation of macromolecules involved in membrane construction. This study represents reports the metabolic characterization of a cell that is perturbed by HMOs.

Ellagic acid derivatives possess antimicrobial and antibiofilm properties across a wide-range of bacterial pathogens. Due to their poor solubility and ambident reactivity it is challenging to synthesize, purify, and characterize the activity of ellagic acid glycosides. In this study, we have synthesized three ellagic acid glycoconjugates and evaluated their antimicrobial and antibiofilm activity in Streptococcus agalactiae (Group B Streptococcus, GBS). Their significant impacts on biofilm formation were examined via scanning electron microscopy (SEM) to reveal early-stage inhibition of cellular adhesion. Additionally, the synthetic glycosides were evaluated against five of the six ESKAPE pathogens and two fungal pathogens. These studies reveal that the ellagic acid glycosides possess inhibitory effects on the growth of Gram-negative pathogens.

Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is the synthesis of miltefosine, the lone oral drug approved to treat leishmaniasis. Due to its prohibitive expense ($1500 per g), miltefosine is not accesable for the majority of the world's patients. Based on the described reaction sequence, this drug can be produced for $25 per g.