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  • Journal article
    Zhong W, Shi Z, Mahadevegowda SH, Liu B, Zhang K, Hui Koh C, Ruan L, Chen Y, Zeden MS, Pee CJE, Marimuthu K, Pratim De P, Tek Ng O, Zhu Y, Chi YR, Hammond PT, Yang L, Gan Y-H, Pethe K, Greenberg EP, Grundling A, Chan-Park MBet al., 2020,

    Designer broad-spectrum polyimidazolium antibiotics

    , Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 31376-31385, ISSN: 0027-8424

    For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.
  • Journal article
    Williams TC, Jackson DJ, Maltby S, Walton RP, Ching Y-M, Glanville N, Singanayagam A, Brewins JJ, Clarke D, Hirsman AG, Loo S-L, Wei L, Beale JE, Casolari P, Caramori G, Papi A, Belvisi M, Wark PAB, Johnston SL, Edwards MR, Bartlett NWet al., 2020,

    Rhinovirus-induced CCL17 and CCL22 in asthma exacerbations and differential regulation by STAT6.

    , American Journal of Respiratory Cell and Molecular Biology, Vol: 64, Pages: 344-356, ISSN: 1044-1549

    The interplay of type-2 inflammation and anti-viral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma, however mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild-to-moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then employed to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface (ALI) differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression: increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6 which was required for CCL17, but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-kB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, findings suggest therapeutic targeting of type-2-STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.
  • Journal article
    Zhong Q, Roumeliotis T, Kozik Z, Cepeda-Molero M, Angel Fernandez L, Shenoy AR, Bakal C, Frankel G, Choudhary JSet al., 2020,

    Clustering of Tir during enteropathogenic E. coli infection triggers calcium influx-dependent pyroptosis in intestinal epithelial cells

    , PLoS Biology, Vol: 18, ISSN: 1544-9173

    Clustering of the enteropathogenic Escherichia coli (EPEC) type III secretion system (T3SS) effector translocated intimin receptor (Tir) by intimin leads to actin polymerisation and pyroptotic cell death in macrophages. The effect of Tir clustering on the viability of EPEC-infected intestinal epithelial cells (IECs) is unknown. We show that EPEC induces pyroptosis in IECs in a Tir-dependent but actin polymerisation-independent manner, which was enhanced by priming with interferon gamma (IFNγ). Mechanistically, Tir clustering triggers rapid Ca2+ influx, which induces lipopolysaccharide (LPS) internalisation, followed by activation of caspase-4 and pyroptosis. Knockdown of caspase-4 or gasdermin D (GSDMD), translocation of NleF, which blocks caspase-4 or chelation of extracellular Ca2+, inhibited EPEC-induced cell death. IEC lines with low endogenous abundance of GSDMD were resistant to Tir-induced cell death. Conversely, ATP-induced extracellular Ca2+ influx enhanced cell death, which confirmed the key regulatory role of Ca2+ in EPEC-induced pyroptosis. We reveal a novel mechanism through which infection with an extracellular pathogen leads to pyroptosis in IECs.
  • Journal article
    Zheng W, Pena A, Low WW, Wong JLC, Frankel G, Egelman EHet al., 2020,

    Cryoelectron-Microscopic Structure of the pKpQIL Conjugative Pili from Carbapenem-Resistant <i>Klebsiella pneumoniae</i>

    , STRUCTURE, Vol: 28, Pages: 1321-+, ISSN: 0969-2126
  • Journal article
    Alzahabi KH, Usmani O, Georgiou TK, Ryan MP, Robertson BD, Tetley TD, Porter AEet al., 2020,

    Approaches to treating tuberculosis by encapsulating metal ions and anti-mycobacterial drugs utilizing nano- and microparticle technologies

    , Emerging Topics in Life Sciences, Vol: 4, Pages: 581-600, ISSN: 2397-8554

    Tuberculosis (TB) is caused by a bacterial infection that affects a number of human organs, primarily the lungs, but also the liver, spleen, and spine, causing key symptoms of fever, fatigue, and persistent cough, and if not treated properly, can be fatal. Every year, 10 million individuals become ill with active TB resulting with a mortality approximating 1.5 million. Current treatment guidelines recommend oral administration of a combination of first-line anti-TB drugs for at least 6 months. While efficacious under optimum conditions, ‘Directly Observed Therapy Short-course’ (DOTS) is not without problems. The long treatment time and poor pharmacokinetics, alongside drug side effects lead to poor patient compliance and has accelerated the emergence of multi-drug resistant (MDR) organisms. All this, combined with the limited number of newly discovered TB drugs to treat MDR-TB and shorten standard therapy time, has highlighted the need for new targeted drug delivery systems. In this respect, there has been recent focus on micro- and nano-particle technologies to prepare organic or/and metal particles loaded with TB drugs to enhance their efficacy by targeted delivery via the inhaled route. In this review, we provide a brief overview of the current epidemiology of TB, and risk factors for progression of latent stage tuberculosis (LTBI) to the active TB. We identify current TB treatment regimens, newly discovered TB drugs, and identify studies that have used micro- or nano-particles technologies to design a reliable inhalation drug delivery system to treat TB more effectively.
  • Journal article
    Farne H, Singanayagam A, 2020,

    Why asthma might surprisingly protect against poor outcomes in COVID-19

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936
  • Journal article
    Rismondo J, Haddad TFM, Shen Y, Loessner MJ, Grundling Aet al., 2020,

    GtcA is required for LTA glycosylation in Listeria monocytogenes serovar 1/2a and Bacillus subtilis

    , The Cell Surface, Vol: 6, ISSN: 2468-2330

    The cell wall polymers wall teichoic acid (WTA) and lipoteichoic acid (LTA) are often modified with glycosyl and D-alanine residues. Recent studies have shown that a three-component glycosylation system is used for the modification of LTA in several Gram-positive bacteria including Bacillus subtilis and Listeria monocytogenes. In the L. monocytogenes 1/2a strain 10403S, the cytoplasmic glycosyltransferase GtlA is thought to use UDP-galactose to produce the C55-P-galactose lipid intermediate, which is transported across the membrane by an unknown flippase. Next, the galactose residue is transferred onto the LTA backbone on the outside of the cell by the glycosyltransferase GtlB. Here we show that GtcA is necessary for the glycosylation of LTA in L. monocytogenes 10403S and B. subtilis 168 and we hypothesize that these proteins act as C55-P-sugar flippases. With this we revealed that GtcA is involved in the glycosylation of both teichoic acid polymers in L. monocytogenes 10403S, namely WTA with N-acetylglucosamine and LTA with galactose residues. These findings indicate that the L. monocytogenes GtcA protein can act on different C55-P-sugar intermediates. Further characterization of GtcA in L. monocytogenes led to the identification of residues essential for its overall function as well as residues, which predominately impact WTA or LTA glycosylation.
  • Journal article
    Singanayagam A, Johnston SL, 2020,

    Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks

    , JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 146, Pages: 1292-1294, ISSN: 0091-6749
  • Journal article
    Pagani N, Armstrong-James D, Reed A, 2020,

    Successful salvage therapy for fungal bronchial anastomotic infection after-lung transplantation with an inhaled triazole anti-fungal PC945

    , JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 39, Pages: 1505-1506, ISSN: 1053-2498
  • Journal article
    Frosini SM, Bond R, McCarthy AJ, Feudi C, Schwarz S, Lindsay JA, Loeffler Aet al., 2020,

    Genes on the Move: In Vitro Transduction of Antimicrobial Resistance Genes between Human and Canine Staphylococcal Pathogens

    , MICROORGANISMS, Vol: 8

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