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Journal articleEades CP, Armstrong-James DPH, 2019,
Invasive fungal infections in the immunocompromised host: Mechanistic insights in an era of changing immunotherapeutics
, Medical Mycology, Vol: 57, Pages: S307-S317, ISSN: 1369-3786The use of cytotoxic chemotherapy in the treatment of malignant and inflammatory disorders is beset by considerable adverse effects related to nonspecific cytotoxicity. Accordingly, a mechanistic approach to therapeutics has evolved in recent times with small molecular inhibitors of intracellular signaling pathways involved in disease pathogenesis being developed for clinical use, some with unparalleled efficacy and tolerability. Nevertheless, there are emerging concerns regarding an association with certain small molecular inhibitors and opportunistic infections, including invasive fungal diseases. This is perhaps unsurprising, given that the molecular targets of such agents play fundamental and multifaceted roles in orchestrating innate and adaptive immune responses. Nevertheless, some small molecular inhibitors appear to possess intrinsic antifungal activity and may therefore represent novel therapeutic options in future. This is particularly important given that antifungal resistance is a significant, emerging concern. This paper is a comprehensive review of the state-of-the-art in the molecular immunology to fungal pathogens as applied to existing and emerging small molecular inhibitors.
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Journal articleMylona E, Frankel G, 2019,
The S. Typhi effector StoD is an E3 ubiquitin ligase which binds K48- and K63-linked di-ubiquitin
, Life Science Alliance, Vol: 2, ISSN: 2575-1077Salmonella enterica (e.g., serovars Typhi and Typhimurium) relies on translocation of effectors via type III secretion systems (T3SS). Specialization of typhoidal serovars is thought to be mediated via pseudogenesis. Here, we show that the Salmonella Typhi STY1076/t1865 protein, named StoD, a homologue of the enteropathogenic Escherichia coli/enterohemorrhagic E. coli/Citrobacter rodentium NleG, is a T3SS effector. The StoD C terminus (StoD-C) is a U-box E3 ubiquitin ligase, capable of autoubiquitination in the presence of multiple E2s. The crystal structure of the StoD N terminus (StoD-N) at 2.5 Å resolution revealed a ubiquitin-like fold. In HeLa cells expressing StoD, ubiquitin is redistributed into puncta that colocalize with StoD. Binding assays showed that StoD-N and StoD-C bind the same exposed surface of the β-sheet of ubiquitin, suggesting that StoD could simultaneously interact with two ubiquitin molecules. Consistently, StoD interacted with both K63- (KD = 5.6 ± 1 μM) and K48-linked diubiquitin (KD = 15 ± 4 μM). Accordingly, we report the first S. Typhi–specific T3SS effector. We suggest that StoD recognizes and ubiquitinates pre-ubiquitinated targets, thus subverting intracellular signaling by functioning as an E4 enzyme.
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Conference paperSelvarajah U, Blanco JM, Radhakrishnan S, et al., 2019,
IS AXIAL SPONDYLOARTHRITIS IN IBD DIFFERENT TO AXIAL SPONDYLOARTHRITIS WITHOUT IBD?
, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A96-A96, ISSN: 0017-5749 -
Conference paperSelvarajah U, Blanco JM, Radhakrishnan S, et al., 2019,
FAECAL CALPROTECTINSUGGESTS PRESENCE OF GUT INFLAMMATION IN AXIAL SPONDYLOARTHRITIS WITHOUT IBD
, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A95-A95, ISSN: 0017-5749 -
Journal articleEvans LE, Krishna A, Ma Y, et al., 2019,
Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug.
, Journal of Medicinal Chemistry, Vol: 62, Pages: 4411-4425, ISSN: 0022-2623Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic pro-drug that combines ciprofloxacin with a β-lactamase-cleavable motif. The pro-drug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically-relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our pro-drug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.
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Journal articleSinganayagam A, Loo S-L, Calderazzo M, et al., 2019,
Anti-microbial immunity is impaired in COPD patients with frequent exacerbations
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations.<jats:italic>Ex vivo</jats:italic>immune responses to rhinovirus infection in differentiated bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Frequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. RV-induction of interferon and ISGs<jats:italic>ex vivo</jats:italic>was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators also had reduced sputum levels of the anti-microbial peptide mannose-binding lectin (MBL)-2 with an associated increase in sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. MBL-2 levels correlated negatively with bacterial loads during exacerbation.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These data imp
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Journal articleMcKenney PT, Yan J, Vaubourgeix J, et al., 2019,
Intestinal bile acids induce a morphotype switch in vancomycin-resistant enterococcus that facilitates intestinal colonization
, Cell Host and Microbe, Vol: 25, Pages: 695-705.e5, ISSN: 1931-3128Vancomycin-resistant Enterococcus (VRE) are highly antibiotic-resistant and readily transmissible pathogens that cause severe infections in hospitalized patients. We discovered that lithocholic acid (LCA), a secondary bile acid prevalent in the cecum and colon of mice and humans, impairs separation of growing VRE diplococci, causing the formation of long chains and increased biofilm formation. Divalent cations reversed this LCA-induced switch to chaining and biofilm formation. Experimental evolution in the presence of LCA yielded mutations in the essential two-component kinase yycG/walK and three-component response regulator liaR that locked VRE in diplococcal mode, impaired biofilm formation, and increased susceptibility to the antibiotic daptomycin. These mutant VRE strains were deficient in host colonization because of their inability to compete with intestinal microbiota. This morphotype switch presents a potential non-bactericidal therapeutic target that may help clear VRE from the intestines of dominated patients, as occurs frequently during hematopoietic stem cell transplantation.
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Journal articleSchuster C, Howard S, Grundling A, 2019,
Use of the counter selectable marker PheS* for genome engineering in Staphylococcus aureus
, Microbiology, Vol: 165, Pages: 572-584, ISSN: 1350-0872The gold standard tocreate gene deletions in Staphylococcus aureusis by homologous 16recombination using allelic exchange plasmids with a temperature sensitive origin of replication. A knockout vectorthat containsregions of homologyis first integrated into thechromosome of S. aureus by a single crossover event selected for at high temperatures (non-permissive for plasmid replication) and antibiotic selection. Next, the second crossover event is encouraged by 20growth without antibiotic selection at lowtemperature, leading at a certain frequencyto the excision of the plasmid and deletionof the gene of interest.To detector encourage plasmid loss, either a beta-galactosidase screening method or more typically, a counter selection step is used. We here present the adaption of the counter selectable markerpheS*, coding for a mutated subunit of the phenylalanine-tRNA-synthetase for use in S. aureus. The PheS* protein variant allows for the incorporation of the toxic phenylalanine amino acid analoguepara-chlorophenylalanine(PCPA)into proteins and the addition of 20-40 m M PCPAto rich medialeads to a drasticgrowth reductionof S. aureus and supplementing chemically defined medium with 2.5-5 mM PCPA to a complete growth inhibition. Using the new allelic exchange plasmid pIMAY*, wedeletedthe magnesium transporter gene mgtEin S. aureusUSA300 LAC*(SAUSA300_0910/ SAUSA300_RS04895) and RN4220(SAOUHSC_00945) and demonstrate that cobalt toxicity in S. aureusis mainly mediated by the presence of MgtE.This new plasmid will aidto efficiently and easily create gene knockouts in S. aureus.
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Journal articleHaag AF, Fitzgerald JR, Penades JR, 2019,
Staphylococcus aureus in Animals
, Microbiology Spectrum, Vol: 7, Pages: 1-19, ISSN: 2165-0497Staphylococcus aureus is a mammalian commensal and opportunistic pathogen that colonizes niches such as skin, nares and diverse mucosal membranes of about 20-30% of the human population. S. aureus can cause a wide spectrum of diseases in humans and both methicillin-sensitive and methicillin-resistant strains are common causes of nosocomial- and community-acquired infections. Despite the prevalence of literature characterising staphylococcal pathogenesis in humans, S. aureus is a major cause of infection and disease in a plethora of animal hosts leading to a significant impact on public health and agriculture. Infections in animals are deleterious to animal health, and animals can act as a reservoir for staphylococcal transmission to humans.Host-switching events between humans and animals and amongst animals are frequent and have been accentuated with the domestication and/or commercialisation of specific animal species. Host-switching is typically followed by subsequent adaptation through acquisition and/or loss of mobile genetic elements such as phages, pathogenicity islands and plasmids as well as further host-specific mutations allowing it to expand into new host populations.In this chapter, we will be giving an overview of S. aureus in animals, how this bacterial species was, and is, being transferred to new host species and the key elements thought to be involved in its adaptation to new ecological host niches. We will also highlight animal hosts as a reservoir for the development and transfer of antimicrobial resistance determinants.
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Journal articleRebollo-Ramirez S, Larrouy-Maumus G, 2019,
NaCl triggers the CRP-dependent increase of cAMP in Mycobacterium tuberculosis
, Tuberculosis, Vol: 116, Pages: 8-16, ISSN: 1472-9792The second messenger 3′,5′-cyclic adenosine monophosphate (3′,5′-cAMP) has been shown to be involved in the regulation of many biological processes ranging from carbon catabolite repression in bacteria to cell signalling in eukaryotes. In mycobacteria, the role of cAMP and the mechanisms utilized by the bacterium to adapt to and resist immune and pharmacological sterilization remain poorly understood. Among the stresses encountered by bacteria, ionic and non-ionic osmotic stresses are among the best studied. However, in mycobacteria, the link between ionic osmotic stress, particularly sodium chloride, and cAMP has been relatively unexplored. Using a targeted metabolic analysis combined with stable isotope tracing, we show that the pathogenic Mycobacterium tuberculosis but not the opportunistic pathogen Mycobacterium marinum nor the non-pathogenic Mycobacterium smegmatis responds to NaCl stress via an increase in intracellular cAMP levels. We further showed that this increase in cAMP is dependent on the cAMP receptor protein and in part on the threonine/serine kinase PnkD, which has previously been associated with the NaCl stress response in mycobacteria.
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