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In adults, liver-resident macrophages, or Kupffer cells (KCs), reside in the sinusoids and sterilize circulating blood by capturing rapidly flowing microbes. We developed quantitative intravital imaging of 1-day-old mice combined with transcriptomics, genetic manipulation, and in vivo infection assays to interrogate increased susceptibility of newborns to bloodstream infections. Whereas 1-day-old KCs were better at catching Escherichia coli in vitro, we uncovered a critical 1-week window postpartum when KCs have limited access to blood and must translocate from liver parenchyma into the sinusoids. KC migration was independent of the microbiome but depended on macrophage migration inhibitory factor, its receptor CD74, and the adhesion molecule CD44. On the basis of our findings, we propose a model of progenitor macrophage seeding of the liver sinusoids via a reverse transmigration process from liver parenchyma. These results also illustrate the importance of developing newborn mouse models to understand newborn immunity and disease. Editor's summary: Newborns are particularly vulnerable to bloodstream bacterial infections that can lead to meningitis, but the mechanisms underlying this susceptibility are not fully understood. Using real-time intravital microscopy of neonatal mice, Araujo David et al. found that relocalization of Kupffer cells (KCs) from the liver parenchyma into sinusoids during the first week of life coincides with improved clearance of bloodstream bacteria. KC migration into liver sinusoids required macrophage migration inhibitory factor and its receptor CD74 but was independent of the microbiome. These findings demonstrate that delayed KC seeding of the liver sinusoids postnatally may underlie the increased susceptibility to bloodstream infections in newborns. —Claire Olingy [ABSTRACT FROM AUTHOR]

Small colony variants (SCVs) of Staphylococcus aureus are a relatively rare but clinically significant growth morphotype. Infections with SCVs are frequently difficult to treat, inherently antibiotic-resistant, and can lead to persistent infections. Despite a long history of research, the molecular underpinnings of this morphotype and their impact on the clinical trajectory of infections remain unclear. However, a growing body of literature indicates that SCVs are caused by a diverse range of molecular factors. These recent findings suggest that SCVs should be thought of as an ensemble collection of loosely related phenotypes, and not as a single phenomenon. This review describes the diverse mechanisms currently known to contribute to SCVs and proposes an ensemble model for conceptualizing this morphotype., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Novel antimicrobial agents are needed to combat antimicrobial resistance. This study tested novel pentafluorosulfanyl-containing triclocarban analogs for their potential antibacterial efficacy. Standard procedures were used to produce pentafluorosulfanyl-containing triclocarban analogs. Twenty new compounds were tested against seven Gram-positive and Gram-negative indicator strains as well as 10 clinical isolates for their antibacterial and antibiofilm activity. Mechanistic investigations focused on damage to cell membrane, oxidizing reduced thiols, iron-sulfur clusters, and oxidative stress to explain the compounds' activity. Safety profiles were assessed using cytotoxicity experiments in eukaryotic cell lines. Following screening, selected components had significantly better antibacterial and antibiofilm activity against Gram-positive bacteria in lower concentrations in comparison to ciprofloxacin and gentamycin. For instance, one compound had a minimum inhibitory concentration of <0.0003 mM, but ciprofloxacin had 0.08 mM. Mechanistic studies show that these novel compounds do not affect reduced thiol content, iron-sulfur clusters, or hydrogen peroxide pathways. Their impact comes from Gram-positive bacterial cell membrane damage. Tests on cell culture toxicity and host component safety showed promise. Novel diarylurea compounds show promise as Gram-positive antimicrobials. These compounds offer prospects for study and optimization., Importance: The rise of antibiotic resistance among bacterial pathogens poses a significant threat to global health, underscoring the urgent need for novel antimicrobial agents. This study presents research on a promising class of novel compounds with potent antibacterial properties against Gram-positive bacteria, notably Staphylococcus aureus and MRSA . What sets these novel analogs apart is their superior efficacy at substantially lower concentrations compared with commonly used antibiotics like ciprofloxacin and gentamycin. Importantly, these compounds act by disrupting the bacterial cell membrane, offering a unique mechanism that could potentially circumvent existing resistance mechanisms. Preliminary safety assessments also highlight their potential for therapeutic use. This study not only opens new avenues for combating antibiotic-resistant infections but also underscores the importance of innovative chemical approaches in addressing the global antimicrobial resistance crisis., Competing Interests: The authors declare no conflict of interest.