Dataset Information

Non-transpeptidase binding arylthioether ?-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis.

ABSTRACT: The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, ?-lactamase resistant monocyclic ?-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine ?-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) ?-lactamase producing Moraxella catarrhalis clinical isolates.

SUBMITTER: Beck TN

PROVIDER: S-EPMC6415315 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Publications

Non-transpeptidase binding arylthioether β-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis.

Beck Tim N TN Lloyd Dina D Kuskovsky Rostislav R Minah Jeanette J Arora Kriti K Plotkin Balbina J BJ Green Jacalyn M JM Boshoff Helena I HI Barry Clifton C Deschamps Jeffrey J Konaklieva Monika I MI

Bioorganic & medicinal chemistry 20141212 3

The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, β-lactamase resistant monocyclic β-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine β-lactamase producing Mycobacterium tuberculosis wild type strain ...[more]

PMID: 25549898

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Project description:Moraxella catarrhalis is an important pathogen that often causes otitis media in children, a disease that is not currently vaccine preventable. Asymptomatic colonisation of the human upper respiratory tract is common and lack of clearance by the immune system is likely due to the emergence of seroresistant genetic lineages. No active bacteriophages or prophages have been described in this species. This study was undertaken to identify and categorise prophages in M. catarrhalis, their genetic diversity and the relationship of such diversity with the host-species phylogeny.This study presents a comparative analysis of 32 putative prophages identified in 95 phylogenetically variable, newly sequenced M. catarrhalis genomes. The prophages were genotypically classified into four diverse clades. The genetic synteny of each clade is similar to the group 1 phage family Siphoviridae, however, they form genotypic clusters that are distinct from other members of this family. No core genetic sequences exist across the 32 prophages despite clades 2, 3, and 4 sharing the most sequence identity. The analysis of non-structural prophage genes (coding the integrase, and terminase), and portal gene showed that the respective genes were identical for clades 2, 3, and 4, but unique for clade 1. Empirical analysis calculated that these genes are unexpectedly hyperconserved, under purifying selection, suggesting a tightly regulated functional role. As such, it is improbable that the prophages are decaying remnants but stable components of a fluctuating, flexible and unpredictable system ultimately maintained by functional constraints on non-structural and packaging genes. Additionally, the plate encoding genes were well conserved across all four prophage clades, and the tail fibre genes, commonly responsible for receptor recognition, were clustered into three major groups distributed across the prophage clades. A pan-genome of 283,622 bp was identified, and the prophages were mapped onto the diverse M. catarrhalis multi-locus sequence type (MLST) backbone.This study has provided the first evidence of putatively mobile prophages in M. catarrhalis, identifying a diverse and fluctuating system dependent on the hyperconservation of a few key, non-structural genes. Some prophages harbour virulence-related genes, and potentially influence the physiology and virulence of M. catarrhalis. Importantly our data will provide supporting information on the identification of novel prophages in other species by adding greater weight to the identification of non-structural genes.

Dataset Information

Non-transpeptidase binding arylthioether ?-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis.

Publications

Non-transpeptidase binding arylthioether β-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis.

Similar Datasets

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