<i>Neisseria</i> species as pathobionts in bronchiectasis

Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group.Published versio

Controlled delivery of paclitaxel from micro-porous foams for the postsurgical treatment of glioma blastoma multiforme

AIChE Annual Meeting, Conference Proceedings

Paclitaxel delivery from PLGA foams for controlled release in post-surgical chemotherapy against glioblastoma multiforme

10.1016/j.biomaterials.2009.02.030Biomaterials30183189-3196BIMA

Genome sequence of a complex HIV-1 unique recombinant form involving CRF01_AE, subtype B, and subtype B' identified in Malaysia

10.1128/genomeA.00139-14Genome Announcements22e00139-1

Genome sequence of complex HIV-1 unique recombinant forms sharing a common recombination breakpoint identified in Malaysia

10.1128/genomeA.01220-15Genome Announcements36e012201

Screening and characterization of microbial inhibitors against eukaryotic protein phosphatases (PP1 and PP2A)

Aim: To identify novel microbial inhibitors of protein phosphatase 1 (PP1). Methods and Results: 750 actinomycetes and 408 microfungi were isolated from Sabah forest soils and screened for production of potential PP1 inhibitors using an in vivo screening system, in which candidate inhibitors were identified through mimicking the properties of PP1-deficient yeast cells. Acetone extracts of two fungi, H9318 (Penicillium) and H9978 (non-Penicillium) identified in this way showed inhibitory activity towards both mammalian PP1 and PP2A in an in vitro phosphatase assay, while extract from H7520 (Streptomyces) inhibited PP2A but not PP1. Consistently, using a drug-induced haploinsufficiency test, strains with either reduced PP1 or PP2A function were hypersensitive to H9318 and H9978 extracts whereas only the latter strain showed hypersensitivity to H7250 extract. H9318 extract was fractionated using RP-HPLC into two active peaks (S1 and S2). A yeast strain with reduced PP1 function showed hypersensitivity to fraction S2 whereas a strain with reduced PP2A function was hypersensitive to fraction S1. However, S1 and S2 inhibited both PP1 and PP2A activities to a similar extent. Conclusion: Three candidate PP inhibitors have been identified. Significance and Impact of the Study : Further development may generate useful research tools and ultimately therapeutic agents

Multidrug-resistant tuberculosis outbreak in gaming centers, Singapore, 2012

10.3201/eid2101.141159Emerging Infectious Diseases211179-18

Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria

Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of the lipopolysaccharide modification pathways that confer polymyxin resistance. Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillinresistant S. aureus), and vancomycin-resistant Enterococcus faecium. Using the globally disseminated M1T1 GAS strain 5448 as a proof of principle model, colistin in the presence of PBT2 + zinc was shown to be bactericidal in activity. Any resistance that did arise imposed a substantial fitness cost. PBT2 + zinc dysregulated GAS metal ion homeostasis, notably decreasing the cellular manganese content. Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection. These findings provide a foundation from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections.David M. P. De Oliveira, Bernhard Keller, Andrew J. Hayes, Cheryl-Lynn Y. Ong, Nichaela Harbison-Price, Ibrahim M. El-Deeb, Gen Li, Nadia Keller, Lisa Bohlmann, Stephan Brouwer, Andrew G. Turner, Amanda J. Cork, Thomas R. Jones, David L. Paterson, Alastair G. McEwan, Mark R. Davies, Christopher A. McDevitt, Mark von Itzstein, and Mark J. Walke