Highlights d Cities possess a consistent ''core'' set of non-human microbes d Urban microbiomes echo important features of cities and city-life d Antimicrobial resistance genes are widespread in cities d Cities contain many novel bacterial and viral species

Recent studies have revealed that the gut microbiota modulates brain development and behavior, but the underlying mechanisms are still poorly understood. Here, we show that bacterial peptidoglycan (PGN) derived from the commensal gut microbiota can be translocated into the brain and sensed by specific pattern-recognition receptors (PRRs) of the innate immune system. Using expression-profiling techniques, we demonstrate that two families of PRRs that specifically detect PGN (that is, PGN-recognition proteins and NOD-like receptors), and the PGN transporter PepT1 are highly expressed in the developing brain during specific windows of postnatal development in both males and females. Moreover, we show that the expression of several PGN-sensing molecules and PepT1 in the developing striatum is sensitive to manipulations of the gut microbiota (that is, germ-free conditions and antibiotic treatment). Finally, we used the PGN-recognition protein 2 (Pglyrp2) knockout mice to examine the potential influence of PGN-sensing molecules on brain development and behavior. We demonstrate that the absence of Pglyrp2 leads to alterations in the expression of the autism risk gene c-Met, and sex-dependent changes in social behavior, similar to mice with manipulated microbiota. These findings suggest that the central activation of PRRs by microbial products could be one of the signaling pathways mediating the communication between the gut microbiota and the developing brain.

Finding optimal dosing strategies for treating bacterial infections is extremely difficult, and improving therapy requires costly and time-intensive experiments. To date, an incomplete mechanistic understanding of drug effects has limited our ability to make accurate quantitative predictions of drug-mediated bacterial killing and impeded the rational design of antibiotic treatment strategies. Three poorly understood phenomena complicate predictions of antibiotic activity: post-antibiotic growth suppression, density-dependent antibiotic effects, and persister cell formation. Here, we show that chemical binding kinetics alone are sufficient to explain these three phenomena, using single cell data and time-kill curves of Escherichia coli and Vibrio cholerae exposed to a variety of antibiotics in combination with a theoretical model that links chemical reaction kinetics to bacterial population biology. Our model reproduces existing observations, has a high predictive power across different experimental setups (R2= 0.86), and makes several testable predictions, which we verified in new experiments and by analysing published data from a clinical trial on tuberculosis therapy. While a variety of biological mechanisms have previously been invoked to explain post-antibiotic growth suppression, density-dependent antibiotic effects, and especially persister cell formation, our findings reveal that a simple model which considers only binding kinetics provides a parsimonious and unifying explanation for these three complex, phenotypically distinct behaviours. Current antibiotic and other chemotherapeutic regimens are often based on trial-and-error or expert opinion. Our ‘chemical reaction kinetics’-based approach may inform new strategies, that are based on rational design.

The increasing number of multidrug resistant bacteria has revitalized interest in seeking alternative sources for controlling bacterial infection. Silver nanoparticles (AgNPs), are amongst the most promising candidates due to their wide microbial spectrum of action. In this work, we report on the safety and efficacy of the incorporation of collagen coated AgNPs into collagen hydrogels for tissue engineering.The resulting hybrid materials at [AgNPs] < 0.4 µM retained the mechanical properties and biocompatibility for primary human skin fibroblasts and keratinocytes of collagen hydrogels; they also displayed remarkable anti-infective properties against S. aureus, S. epidermidis, E. coli and P. aeruginosa at considerably lower concentrations than silver nitrate. Further, subcutaneous implants of materials containing 0.2 µM AgNPs in mice showed a reduction in the levels of IL-6 and other inflammation markers (CCL24, sTNFR-2, and TIMP1). Finally, an analysis of silver contents in implanted mice showed that silver accumulation primarily occurred within the tissue surrounding the implant. IntroductionBiomaterial-associated infections are a significant healthcare problem and have been linked to medical morbidity and death. [2][3][4][5][6] This has motivated the development of materials with anti-infective properties, such as biomaterials loaded with antibiotics. 7 However, with the increasing number of bacteria that are resistant to antibiotics, 8 silver with historically documented anti-microbial activity has re-gained its attractiveness as an alternative to antibiotics. 9 While toxic to bacteria, it unfortunately is also toxic to mammalian cells. 9,10 More recently, therefore, silver nanoparticles (AgNPs) have been evaluated as a safer alternative to ionic silver. 1,[11][12][13][14][15][16][17][18][19][20] The recent work from our team showed that in comparison with silver, biomolecule-coated, photochemically-produced AgNPs can have both bactericidal and bacteriostatic properties with almost negligible cytotoxic effects. 12 We also showed that oxidation of Ag to AgO is most likely the cause of the cytotoxic effects observed with AgNPs. Our overarching goal is to expand the safe use of AgNPs in the development of implantable hybrid-biomaterials with antiinfective properties for future use as scaffolds to enable regeneration of tissue and organs at a risk of bacterial colonization and concomitant biofilm formation like diabetic foot ulcers. Although some collagen-based materials including † Electronic supplementary information (ESI) available: Representative absorption spectra of AgNP@collagen nanoparticles before and after lyophilization. Absorption spectra for the washes obtained from a 1.0 µM AgNP hydrogel over the course of 5 days. Area under the curve (AUC) calculated from the absorption spectra of 500 µm thickness collagen hydrogels prepared using different concentrations of AgNP@collagen. Selected Cryo-SEM images of BDDGE type I collagen-based hydrogels in the absence or presence of 1.0 µM AgNP. An image of a sel...

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The structure of the O-antigen from the international reference strain Escherichia coli O93:−:H16 has been determined. A nonrandom modal chain-length distribution was observed for the lipopolysaccharide, a pattern which is typical when long O-specific polysaccharides are expressed. By a combination of (i) bioinformatics information on the gene cluster related to O-antigen synthesis including putative function on glycosyl transferases, (ii) the magnitude of NMR coupling constants of anomeric protons and (iii) unassigned 2D 1H,13C-HSQC and 1H,1H-TOCSY NMR spectra it was possible to efficiently elucidate the structure of the carbohydrate polymer in an automated fashion using the computer program CASPER. The polysaccharide also carries O-acetyl groups and their locations were determined by 2D NMR experiments showing that ~½ of the population was 2,6-di-O-acetylated, ~¼ was 2-O-acetylated, whereas ~¼ did not carry O-acetyl group(s) in the 3-O-substituted mannosyl residue of the repeating unit. The structure of the tetrasaccharide repeating unit of the O-antigen is given by: →2)-β-d-Manp-(1 → 3)-β-d-Manp2Ac6Ac-(1 → 4)-β-d-GlcpA-(1 → 3)-α-d-GlcpNAc-(1→, which should also be the biological repeating unit and it shares structural elements with capsular polysaccharides from E. coli K84 and K50. The structure of the acidic O-specific polysaccharide from Cellulophaga baltica strain NN015840T differs to that of the O-antigen from E. coli O93 by lacking the O-acetyl group at O6 of the O-acetylated mannosyl residue.