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  • Journal article
    Arthur PK, Amarh V, Cramer P, Arkaifie GB, Blessie EJS, Fuseini M-S, Carilo I, Yeboah R, Asare L, Robertson BDet al., 2019,

    Characterization of two new multidrug-resistant strains of mycobacterium smegmatis: tools for routine in vitro screening of novel anti-mycobacterial agents

    , Antibiotics, Vol: 8, ISSN: 2079-6382

    Mycobacterium tuberculosis is a pathogen of global public health concern. This threat is exacerbated by the emergence of multidrug-resistant and extremely-drug-resistant strains of the pathogen. We have obtained two distinct clones of multidrug-resistant Mycobacterium smegmatis after gradual exposure of Mycobacterium smegmatis mc² 155 to increasing concentrations of erythromycin. The resulting resistant strains of Mycobacterium smegmatis exhibited robust viability in the presence of high concentrations of erythromycin and were found to be resistant to a wide range of other antimicrobials. They also displayed a unique growth phenotype in comparison to the parental drug-susceptible Mycobacterium smegmatis mc² 155, and a distinct colony morphology in the presence of cholesterol. We propose that these two multidrug-resistant clones of Mycobacterium smegmatis could be used as model organisms at the inceptive phase of routine in vitro screening of novel antimicrobial agents targeted against multidrug-resistant Mycobacterial tuberculosis.
  • Journal article
    Botella H, Vaubourgeix J, 2019,

    Building walls: Work that never ends

    , Trends in Microbiology, Vol: 27, Pages: 4-7, ISSN: 0966-842X

    Fluorescent amino acid analogs have proven to be useful tools for studying the dynamics of peptidoglycan metabolism. García-Heredia and colleagues showed that their route of incorporation differs depending on the adjunct fluorophore and applied this property to investigate mycobacterial peptidoglycan synthesis and remodeling with heightened granularity.
  • Book chapter
    Haag AF, Ross Fitzgerald J, Penadés JR, 2019,

    Staphylococcus aureus in animals

    , Gram-Positive Pathogens, Pages: 731-746

    The genus Staphylococcus currently comprises 81 species and subspecies (https://www.dsmz.de/bacterial-diversity/prokaryotic-nomenclature-up-to-date/prokaryotic-nomenclature-up-to-date.html), and most members of the genus are mammalian commensals or opportunistic pathogens that colonize niches such as skin, nares, and diverse mucosal membranes. Several species are of significant medical or veterinary importance. Staphylococcus pseudintermedius (1) is a leading cause of pyoderma in dogs and is considered to be a significant reservoir of antimicrobial resistance factors for the genus (2, 3). S. pseudintermedius is very similar to Staphylococcus intermedius and can be distinguished from other coagulase-positive staphylococci by positive arginine dihydrolase and acid production from β-gentiobiose and d-mannitol (4) or by using a multiplex-PCR approach targeting the nuclease gene nuc (5). Staphylococcus saprophyticus is the second leading cause of uncomplicated urinary tract infections (6). While Staphylococcus epidermidis is a normal component of the epidermal microbiota, it is a leading cause of biofilm contamination of medical devices (7). The most promiscuous and most significant human pathogenic staphylococcal species is Staphylococcus aureus, which is the causal agent of a variety of disease symptoms that can range from cosmetic to lethal manifestations. S. aureus is distinguished from most members of the genus by its abundant production of secreted coagulase, an enzyme which converts serum fibrinogen to fibrin and promotes clotting. However, the S. intermedius group and some strains of Staphylococcus lugdunensis have coagulase activity (5, 8, 9).
  • Journal article
    O'Connor G, Krishnan N, Fagan-Murphy A, Cassidy J, O'Leary S, Robertson BD, Keane J, O'Sullivan MP, Cryan S-Aet al., 2019,

    Inhalable poly(lactic-co-glycolic acid) (PLGA) microparticles encapsulating all-trans-Retinoic acid (ATRA) as a host-directed, adjunctive treatment for Mycobacterium tuberculosis infection

    , European Journal of Pharmaceutics and Biopharmaceutics, Vol: 134, Pages: 153-165, ISSN: 0939-6411

    Ending the tuberculosis (TB) epidemic by 2030 was recently listed in the United Nations (UN) Sustainable Development Goals alongside HIV/AIDS and malaria as it continues to be a major cause of death worldwide. With a significant proportion of TB cases caused by resistant strains of Mycobacterium tuberculosis (Mtb), there is an urgent need to develop new and innovative approaches to treatment. Since 1989, researchers have been assessing the anti-bacterial effects of the active metabolite of vitamin A, all trans-Retinoic acid (ATRA) solution, in Mtb models. More recently the antibacterial effect of ATRA has been shown to regulate the immune response to infection via critical gene expression, monocyte activation and the induction of autophagy leading to its application as a host-directed therapy (HDT). Inhalation is an attractive route for targeted treatment of TB, and therefore we have developed ATRA-loaded microparticles (ATRA-MP) within the inhalable size range (2.07 ± 0.5 µm) offering targeted delivery of the encapsulated cargo (70.5 ± 2.3%) to the site of action within the alveolar macrophage, which was confirmed by confocal microscopy. Efficient cellular delivery of ATRA was followed by a reduction in Mtb growth (H37Ra) in THP-1 derived macrophages evaluated by both the BACT/ALERT® system and enumeration of colony forming units (CFU). The antibacterial effect of ATRA-MP treatment was further assessed in BALB/c mice infected with the virulent strain of Mtb (H37Rv). ATRA-MP treatments significantly decreased the bacterial burden in the lungs alongside a reduction in pulmonary pathology following just three doses administered intratracheally. The immunomodulatory effects of targeted ATRA treatment in the lungs indicate a distinct yet effective mechanism of action amongst the formulations. This is the first study to-date of a controlled release ATRA treatment for TB suitable for inhalation that offers improved targeting of a HDT, retains antib
  • Journal article
    Godlee C, Cerny O, durkin C, Holden Det al., 2019,

    SrcA is a chaperone for the Salmonella SPI-2 type three secretion system effector SteD

    , Microbiology, Vol: 165, Pages: 15-25, ISSN: 1350-0872

    Effector proteins of type three secretion systems (T3SS) often require cytosolic chaperones for their stabilization, to interact with the secretion machinery and to enable effector delivery into host cells. We found that deletion of srcA, previously shown to encode a chaperone for the Salmonella pathogenicity island 2 (SPI-2) T3SS effectors SseL and PipB2, prevented the reduction of mature Major Histocompatibility Complex class II (mMHCII) from the surface of antigen-presenting cells during Salmonella infection. This activity was shown previously to be caused by the SPI-2 T3SS effector SteD. Since srcA and steD are located in the same operon on the Salmonella chromosome, this suggested that the srcA phenotype might be due to an indirect effect on SteD. We found that SrcA is not translocated by the SPI-2 T3SS but interacts directly and forms a stable complex with SteD in bacteria with a 2 : 1 stoichiometry. We found that SrcA was not required for SPI-2 T3SS-dependent, neutral pH-induced secretion of either SseL or PipB2 but was essential for secretion of SteD. SrcA therefore functions as a chaperone for SteD, explaining its requirement for the reduction in surface levels of mMHCII.
  • Journal article
    Gollan B, Grabe G, Michaux C, Helaine Set al., 2019,

    Bacterial Persisters and Infection: Past, Present, and Progressing

    , ANNUAL REVIEW OF MICROBIOLOGY, VOL 73, Vol: 73, Pages: 359-385, ISSN: 0066-4227
  • Journal article
    Larrouy-Maumus GJ, 2019,

    Lipids as biomarkers of cancer and bacterial infections

    , Current Medicinal Chemistry, Vol: 26, Pages: 1924-1932, ISSN: 0929-8673

    Lipids are ubiquitous molecules, known to play important roles in various cellular processes. Alterations to the lipidome can therefore be used as a read-out of the signs of disease, highlighting the importance to consider lipids as biomarkers in addition of nucleic acid and proteins. This mini-review exposes the current knowledge and limitations of the use of lipids as biomarkers of the top global killers which are cancer and bacterial infections.
  • Journal article
    Frankel G, Schroeder GN, 2019,

    The Galleria mellonella Infection Model for Investigating the Molecular Mechanisms of Legionella Virulence.

    , Methods Mol Biol, Vol: 1921, Pages: 333-346

    Legionella species evolved virulence factors to exploit protozoa as replicative niches in the environment. Cell culture infection models demonstrated that many of these factors also enable the bacteria to thrive in human macrophages; however, these models do not recapitulate the complex interactions between macrophages, lung epithelial, and additional immune cells, which are crucial to control bacterial infections. Thus, suitable infection models are required to understand which bacterial factors are important to trigger disease. Guinea pigs and, most frequently, mice have been successfully used as mammalian model hosts; however, ethical and economic considerations impede their use in high-throughput screening studies of Legionella isolates or small molecule inhibitors.Here, we describe the larvae of the lepidopteran Galleria mellonella as insect model of Legionella pathogenesis. Larvae can be obtained from commercial suppliers in large numbers, maintained without the need of specialized equipment, and infected by injection. Although lacking the complexity of a mammalian immune system, the larvae mount humoral and cellular immune responses to infection. L. pneumophila strain 130b and other prototype isolates withstand these responses and use the Defective in organelle trafficking/Intracellular multiplication (Dot/Icm) type IV secretion system (T4SS ) to inject effectors enabling survival and replication in hemocytes, insect phagocytes, ultimately leading to the death of the larvae. Differences in virulence between L. pneumophila isolates or gene deletion mutants can be analyzed using indicators of larval health and immune induction, such as pigmentation, mobility, histopathology, and survival. Bacterial replication can be measured by plating hemolymph or by immunofluorescence microscopy of isolated circulating hemocytes from infected larvae. Combined, these straightforward experimental readouts make G. mellonella larvae a versatile model host to rapidly assess the v
  • Journal article
    So EC, Mousnier A, Frankel G, Schroeder GNet al., 2019,

    Determination of In Vivo Interactomes of Dot/Icm Type IV Secretion System Effectors by Tandem Affinity Purification.

    , Methods Mol Biol, Vol: 1921, Pages: 289-303

    The Dot/Icm type IV secretion system (T4SS) is essential for the pathogenesis of Legionella species and translocates a multitude of effector proteins into host cells. The identification of host cell targets of these effectors is often critical to unravel their roles in controlling the host. Here we describe a method to characterize the protein complexes associated with effectors in infected host cells. To achieve this, Legionella expressing an effector of interest fused to a Bio-tag, a combination of hexahistidine tags and a specific recognition sequence for the biotin ligase BirA, are used to infect host cells expressing BirA, which leads to biotinylation of the translocated effector. Following chemical cross-linking, effector interactomes are isolated by tandem affinity purification employing metal affinity and NeutrAvidin resins and identified by western blotting or mass spectrometry.
  • Book chapter
    Costa TRD, Francis MK, Farag SI, Edgren T, Francis MSet al., 2019,

    Measurement of Yersinia Translocon Pore Formation in Erythrocytes

    , Methods in Molecular Biology, Publisher: Springer New York, Pages: 211-229, ISBN: 9781493995400

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