The continuing emergence of multi-drug resistant pathogens has sparked an interest in seeking alternative therapeutic options. Antimicrobial combinatorial therapy is one such avenue. A number of ...studies have been conducted, involving combinations of bacteriocins with other antimicrobials, to circumvent the development of antimicrobial resistance and/or increase antimicrobial potency. Such bacteriocin-antimicrobial combinations could have tremendous value, in terms of reducing the likelihood of resistance development due to the involvement of two distinct mechanisms of antimicrobial action. Furthermore, antimicrobial synergistic interactions may also have potential financial implications in terms of decreasing the costs of treatment by reducing the concentration of an expensive antimicrobial and utilizing it in combination with an inexpensive one. In addition, combinatorial therapies with bacteriocins can broaden antimicrobial spectra and/or result in a reduction in the concentration of an antibiotic required for effective treatments to the extent that potentially toxic or adverse side effects can be reduced or eliminated. Here, we review studies in which bacteriocins were found to be effective in combination with other antimicrobials, with a view to targeting clinical and/or food-borne pathogens. Furthermore, we discuss some of the bottlenecks which are currently hindering the development of bacteriocins as viable therapeutic options, as well as addressing the need to exercise caution when attempting to predict clinical outcomes of bacteriocin-antimicrobial combinations.
Human milk provides complete nutrition for infants and at the same time promotes the growth of specific bacteria in the infant gastrointestinal tract. Breastfeeding can often be discontinued due to ...mastitis which is an inflammation of the breast tissue. We isolated 18 Staphylococcus aureus strains from milk donated by healthy (n = 6), subclinical (n = 6), and mastitic (n = 6) mothers, two strains of which were VISA (Vancomycin Intermediate S. aureus). All tested strains (n = 12) were able to form biofilms. We then examined the impact of nisin A and vancomycin alone and in combination on biofilm formation and eradication of selected strains (n = 8). We observed strain-specific responses, with the combinatorial treatment at 1/4X MIC (for both singularly) significantly inhibiting biofilm formation for seven out of eight strains when compared with nisin A or vancomycin alone. None of the selected treatments were able to eradicate pre-formed biofilms. Finally, we selected two strains, namely a VISA (APC3814H) and a strong biofilm former (APC3912CM) and used confocal microscopy to evaluate the effects of the antimicrobial agents at 1X MIC on biofilm inhibition and eradication. All treatments inhibited biofilm formation of APC3814H but were ineffective in eradicating a pre-formed biofilm. Single treatments at 1X MIC against APC3912CM cells did not prevent biofilm formation whereas combination treatment caused increased death of APC3912CM cells. Finally, the combination treatment reduced the thickness of the pre-formed APC3912CM biofilm as compared with the single treatments.
Cloud horizontal size distributions from near-global satellite data, from aircraft, and from a global high-resolution numerical weather prediction model, are presented for the scale range 0.1–8000 km ...and are shown to be well-represented using a single power-law relationship with an exponent ofβ= 1.66 ±0.04 from 0.1 to 1500 km or more. At scales longer than 1500 km, there is a statistically significant scale break with fewer very large clouds than expected from the power law. The size distribution is integrated to determine the contribution to cloud cover and visible reflectance from clouds larger than a given size. Globally, clouds with a horizontal dimension of 200 km or more constitute approximately 50% of the cloud cover and 60% of the reflectance, and this result is not sensitive to the minimum size threshold assumed in the integral assuming that the power law can be extrapolated below 100-m scale. The result is also not sensitive to whether the size distribution is determined using cloud segment length or cloud area. This emphasizes the great role played by large cloud sheets in determining the earth’s albedo. On the other hand, some 15% of global cloud cover comes from clouds smaller than 10 km, thus emphasizing the broad range of cloud sizes that contribute significantly to the earth’s radiation budget. Both of these results stem from the fact thatβis slightly less than 2. The data are further divided and geographical and seasonal variations in the cloud sizeL
50for which clouds larger thanL
50constitute 50% of the cloud cover are determined. The largest clouds (L
50> 300 km) are found over the midlatitude oceans, particularly in summer, and over the tropical convective regions of the west Pacific and Indian Oceans and the monsoon-influenced landmasses. The smallest clouds (L
50< 100 km) are found over the trade wind regions of the tropics/subtropics and over arid land areas. Small variations in the exponentβcontribute significantly to the variations in L50. Finally, it is shown that a bounded cascade model can faithfully simulate the observed cloud size distributions and use this to examine the effects of limiting sensor resolution (pixel size) and domain size (number of pixels across image). Sensor resolution is not found to strongly impact the cloud size distribution provided the ratio of the domain to pixel size remains greater than ∼1000. Thus, previous studies with small domain–pixel size ratios may provide biased information about the true cloud size distribution, and should be interpreted with caution.
A new bulk microphysical parameterization (BMP) has been developed for use with the Weather Research and Forecasting (WRF) Model or other mesoscale models. As compared with earlier single-moment ...BMPs, the new scheme incorporates a large number of improvements to both physical processes and computer coding, and it employs many techniques found in far more sophisticated spectral/bin schemes using lookup tables. Unlike any other BMP, the assumed snow size distribution depends on both ice water content and temperature and is represented as a sum of exponential and gamma distributions. Furthermore, snow assumes a nonspherical shape with a bulk density that varies inversely with diameter as found in observations and in contrast to nearly all other BMPs that assume spherical snow with constant density. The new scheme's snow category was readily modified to match previous research in sensitivity experiments designed to test the sphericity and distribution shape characteristics. From analysis of four idealized sensitivity experiments, it was determined that the sphericity and constant density assumptions play a major role in producing supercooled liquid water whereas the assumed distribution shape plays a lesser, but nonnegligible, role. Further testing using numerous case studies and comparing model results with in situ and other observations confirmed the results of the idealized experiments and are briefly mentioned herein, but more detailed, microphysical comparisons with observations are found in a companion paper in this series (Part III, forthcoming). PUBLICATION ABSTRACT
The skin microbiota is thought to play a key role in host protection from infection. Nisin J is a novel nisin variant produced by
APC 2923, a strain isolated from the toe web space area in a ...screening study performed on the human skin microbiota. Whole-genome sequencing and mass spectrometry of the purified peptide confirmed that
APC 2923 produces a 3,458-Da bacteriocin, designated nisin J, which exhibited antimicrobial activity against a range of Gram-positive pathogens, including methicillin-resistant
(MRSA) and
The gene order in the nisin J gene cluster (
) differs from that of other nisin variants in that it is lacking the nisin regulatory genes,
, as well as the nisin immunity gene
Nisin J has 9 amino acid changes compared to prototypical nisin A, with 8 amino acid substitutions, 6 of which are not present in other nisin variants (Ile4Lys, Met17Gln, Gly18Thr, Asn20Phe, Met21Ala, Ile30Gly, Val33His, and Lys34Thr), and an extra amino acid close to the C terminus, rendering nisin J the only nisin variant to contain 35 amino acids. This is the first report of a nisin variant produced by a
species and the first nisin producer isolated from human skin.
This study describes the characterization of nisin J, the first example of a natural nisin variant, produced by a human skin isolate of staphylococcal origin. Nisin J displays inhibitory activity against a wide range of bacterial targets, including MRSA. This work demonstrates the potential of human commensals as a source for novel antimicrobials that could form part of the solution to antibiotic resistance across a broad range of bacterial pathogens.
Large biases in climate model simulations of cloud radiative properties over the Southern Ocean cause large errors in modeled sea surface temperatures, atmospheric circulation, and climate ...sensitivity. Here, we combine cloud-resolving model simulations with estimates of the concentration of ice-nucleating particles in this region to show that our simulated Southern Ocean clouds reflect far more radiation than predicted by global models, in agreement with satellite observations. Specifically, we show that the clouds that are most sensitive to the concentration of ice-nucleating particles are low-level mixed-phase clouds in the cold sectors of extratropical cyclones, which have previously been identified as a main contributor to the Southern Ocean radiation bias. The very low ice-nucleating particle concentrations that prevail over the Southern Ocean strongly suppress cloud droplet freezing, reduce precipitation, and enhance cloud reflectivity. The results help explain why a strong radiation bias occurs mainly in this remote region away from major sources of ice-nucleating particles. The results present a substantial challenge to climate models to be able to simulate realistic ice-nucleating particle concentrations and their effects under specific meteorological conditions.
Nisin is a bacteriocin widely utilized in more than 50 countries as a safe and natural antibacterial food preservative. It is the most extensively studied bacteriocin, having undergone decades of ...bioengineering with a view to improving function and physicochemical properties. The discovery of novel nisin variants with enhanced activity against clinical and foodborne pathogens has recently been described. We screened a randomized bank of nisin A producers and identified a variant with a serine to glycine change at position 29 (S29G), with enhanced efficacy against S. aureus SA113. Using a site-saturation mutagenesis approach we generated three more derivatives (S29A, S29D and S29E) with enhanced activity against a range of Gram positive drug resistant clinical, veterinary and food pathogens. In addition, a number of the nisin S29 derivatives displayed superior antimicrobial activity to nisin A when assessed against a range of Gram negative food-associated pathogens, including E. coli, Salmonella enterica serovar Typhimurium and Cronobacter sakazakii. This is the first report of derivatives of nisin, or indeed any lantibiotic, with enhanced antimicrobial activity against both Gram positive and Gram negative bacteria.
Gastrointestinal (GI) parasites, hookworms in particular, have evolved to cause minimal harm to their hosts, allowing them to establish chronic infections. This is mediated by creating an ...immunoregulatory environment. Indeed, hookworms are such potent suppressors of inflammation that they have been used in clinical trials to treat inflammatory bowel diseases (IBD) and celiac disease. Since the recent description of helminths (worms) secreting extracellular vesicles (EVs), exosome-like EVs from different helminths have been characterized and their salient roles in parasite-host interactions have been highlighted. Here, we analyze EVs from the rodent parasite
, which has been used as a model for human hookworm infection.
EVs (
-EVs) are actively internalized by mouse gut organoids, indicating a role in driving parasitism. We used proteomics and RNA-Seq to profile the molecular composition of
-EVs. We identified 81 proteins, including proteins frequently present in exosomes (like tetraspanin, enolase, 14-3-3 protein, and heat shock proteins), and 27 sperm-coating protein-like extracellular proteins. RNA-Seq analysis revealed 52 miRNA species, many of which putatively map to mouse genes involved in regulation of inflammation. To determine whether GI nematode EVs had immunomodulatory properties, we assessed their potential to suppress GI inflammation in a mouse model of inducible chemical colitis. EVs from
but not those from the whipworm
or control vesicles from grapes protected against colitic inflammation in the gut of mice that received a single intraperitoneal injection of EVs. Key cytokines associated with colitic pathology (IL-6, IL-1β, IFNγ, and IL-17a) were significantly suppressed in colon tissues from EV-treated mice. By contrast, high levels of the anti-inflammatory cytokine IL-10 were detected in
-EV-treated mice. Proteins and miRNAs contained within helminth EVs hold great potential application in development of drugs to treat helminth infections as well as chronic non-infectious diseases resulting from a dysregulated immune system, such as IBD.
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