Assembly of the Mycobacterial Cell Wall Jankute, Monika; Cox, Jonathan A.G; Harrison, James ...
Annual review of microbiology,
10/2015, Letnik:
69, Številka:
1
Journal Article
Recenzirano
Mycobacterium tuberculosis
remains one of the most successful bacterial pathogens, claiming over 1.3 million lives worldwide in 2013. The emergence of multidrug-resistant and extensively ...drug-resistant isolates has prompted the need for new drugs and drug targets.
M. tuberculosis
possesses an unusual cell wall dominated by lipids and carbohydrates that provides a permeability barrier against hydrophilic drugs and is crucial for its survival and virulence. This large macromolecular structure, termed the mycolyl-arabinogalactan-peptidoglycan complex, and the phosphatidyl-
myo
-inositol-based lipoglycans are key features of the mycobacterial cell wall. Assembly of these cell wall components is an attractive target for the development of chemotherapeutics against tuberculosis. Herein, we focus on recent biochemical and molecular insights into these complex molecules of
M. tuberculosis
cell wall.
Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the ...emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo1,2-apyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1-4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism (937)ACC>(937)GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.
The majority of stars are part of gravitationally bound stellar systems, such as binaries. Observations of protobinary systems constrain the conditions that lead to stellar multiplicity and ...subsequent orbital evolution. We report high-angular resolution observations of the circumbinary disk around BHB2007 11, a young binary protostar system. The two protostars are embedded in circumstellar disks that have radii of 2 to 3 astronomical units and probably contain a few Jupiter masses. These systems are surrounded by a complex structure of filaments connecting to the larger circumbinary disk. We also observe accretion and radio jets associated with the protobinary system. The accretion is preferentially onto the lower-mass protostar, consistent with theoretical predictions.
Mycobacteria are a large family of over 100 species, most of which do not cause diseases in humans. The majority of the mycobacterial species are referred to as nontuberculous mycobacteria (NTM), ...meaning they are not the causative agent of tuberculous (TB) or leprosy, i.e.,
complex and
, respectively. The latter group is undoubtedly the most infamous, with TB infecting an estimated 10 million people and causing over 1.2 million deaths in 2017 alone TB and leprosy also differ from NTM in that they are only transmitted from person to person and have no environmental reservoir, whereas NTM infections are commonly acquired from the environment. It took until the 1950's for NTM to be recognised as a potential lung pathogen in people with underlying pulmonary disease and another three decades for NTM to be widely regarded by the medical community when
complex was identified as the most common group of opportunistic pathogens in AIDS patients. This review focuses on an emerging NTM called
(
).
is a rapidly growing NTM that is responsible for opportunistic pulmonary infections in patients with structural lung disorders such as cystic fibrosis and bronchiectasis, as well as a wide range of skin and soft tissue infections in humans. In this review, we discuss how we came to understand the pathogen, how it is currently treated and examine drug resistance mechanisms and novel treatments currently in development. We highlight the urgent need for new and effective treatments for
infection as well as improved in vivo methods of efficacy testing.
Antimicrobial resistance is dominating scientific media. We are warned of an impending ‘antibiotic apocalypse’, where mankind faces its biggest threat, untreatable microbes. However, the world is not ...ending. Scientists are responding to the threat; new knowledge and chemotherapeutics are being created to safeguard our future. The future is bright, not gloomy.
Changing the Rules of TB-Drug Discovery Harrison, James; Cox, Jonathan A. G
Journal of medicinal chemistry,
12/2019, Letnik:
62, Številka:
23
Journal Article
Recenzirano
Odprti dostop
The discovery of new drugs with novel targets is paramount to the continued success of tuberculosis (TB) treatment due to the increasing prevalence of antibiotic resistant infections in the TB ...population. Mycobacterium tuberculosis (Mtb) fumarate hydratase (fumarase) is a highly conserved essential protein that shares an active site with human fumarase, making active site inhibition equally cytotoxic for both bacteria and humans. The recent discovery of a set of new Mtb inhibitory compounds that target Mtb-fumarase by binding to a nonconserved allosteric site is a major advancement, providing further evidence to dispel the antibiotic discovery dogma that conserved proteins do not make good antibiotic targets.
Changes in the respiratory microbiome are associated with disease progression in idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome remains unknown.
To ...explore the host-microbial interactions in IPF.
Sixty patients diagnosed with IPF were prospectively enrolled together with 20 matched control subjects. Subjects underwent bronchoalveolar lavage (BAL), and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For subjects with IPF, additional samples were taken at 1, 3, and 6 months and (if alive) 1 year. Gene expression profiles were generated using Affymetrix Human Gene 1.1 ST arrays.
By network analysis of gene expression data, we identified two gene modules that strongly associated with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative polymerase chain reaction), and specific microbial operational taxonomic units, as well as with lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defense response include NLRC4, PGLYRP1, MMP9, and DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal overexpression in subjects experiencing disease progression, further strengthening the relationship of the transcripts with disease.
Integrated analysis of the host transcriptome and microbial signatures demonstrated an apparent host response to the presence of an altered or more abundant microbiome. These responses remained elevated in longitudinal follow-up, suggesting that the bacterial communities of the lower airways may act as persistent stimuli for repetitive alveolar injury in IPF.
Honey is a complex sweet food stuff with well-established antimicrobial and antioxidant properties. It has been used for millennia in a variety of applications, but the most noteworthy include the ...treatment of surface wounds, burns and inflammation. A variety of substances in honey have been suggested as the key component to its antimicrobial potential; polyphenolic compounds, hydrogen peroxide, methylglyoxal and bee-defensin 1. These components vary greatly across honey samples due to botanical origin, geographical location and secretions from the bee. The use of medical grade honey in the treatment of surface wounds and burns has been seen to improve the healing process, reduce healing time, reduce scarring and prevent microbial contamination. Therefore, if medical grade honeys were to be included in clinical treatment, it would reduce the demand for antibiotic usage. In this review, we outline the constituents of honey and how they affect antibiotic potential in a clinical setting. By identifying the key components, we facilitate the development of an optimally antimicrobial honey by either synthetic or semisynthetic production methods.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown cause that leads to respiratory failure and death within 5 years of diagnosis. Overt respiratory infection and ...immunosuppression carry a high morbidity and mortality, and polymorphisms in genes related to epithelial integrity and host defense predispose to IPF.
To investigate the role of bacteria in the pathogenesis and progression of IPF.
We prospectively enrolled patients diagnosed with IPF according to international criteria together with healthy smokers, nonsmokers, and subjects with moderate chronic obstructive pulmonary disease as control subjects. Subjects underwent bronchoalveolar lavage (BAL), from which genomic DNA was isolated. The V3-V5 region of the bacterial 16S rRNA gene was amplified, allowing quantification of bacterial load and identification of communities by 16S rRNA quantitative polymerase chain reaction and pyrosequencing.
Sixty-five patients with IPF had double the burden of bacteria in BAL fluid compared with 44 control subjects. Baseline bacterial burden predicted the rate of decline in lung volume and risk of death and associated independently with the rs35705950 polymorphism of the MUC5B mucin gene, a proven host susceptibility factor for IPF. Sequencing yielded 912,883 high-quality reads from all subjects. We identified Haemophilus, Streptococcus, Neisseria, and Veillonella spp. to be more abundant in cases than control subjects. Regression analyses indicated that these specific operational taxonomic units as well as bacterial burden associated independently with IPF.
IPF is characterized by an increased bacterial burden in BAL that predicts decline in lung function and death. Trials of antimicrobial therapy are needed to determine if microbial burden is pathogenic in the disease.
Senescent cells show an altered secretome profile termed the senescence-associated secretory phenotype (SASP). There is an increasing body of evidence that suggests that the accumulation of ...SASP-positive senescent cells in humans is partially causal in the observed shift to a low-level pro-inflammatory state in aged individuals. This in turn suggests the SASP as a possible therapeutic target to ameliorate inflammatory conditions in the elderly, and thus a better understanding of the signalling pathways underlying the SASP are required. Prior studies using the early generation p38 MAPK inhibitor SB203580 indicated that p38 signalling was required for the SASP. In this study, we extend these observations using two next-generation p38 inhibitors (UR-13756 and BIRB 796) that have markedly improved selectivity and specificity compared to SB203580, to strengthen the evidence that the SASP is p38-dependent in human fibroblasts. BIRB 796 has an efficacy and toxicity profile that has allowed it to reach Phase III clinical trials, suggesting its possible use to suppress the SASP in vivo. We also demonstrate for the first time a requirement for signalling through the p38 downstream MK2 kinase in the regulation of the SASP using two MK2 inhibitors. Finally, we demonstrate that a commercially-available multiplex cytokine assay technology can be used to detect SASP components in the conditioned medium of cultured fibroblasts from both young and elderly donors. This assay is a high-throughput, multiplex microtitre-based assay system that is highly sensitive, with very low sample requirements, allowing it to be used for low-volume human biological fluids. Our initial studies using existing multiplex plates form the basis for a “SASP signature” assay that could be used as a high-throughput system in a clinical study setting. Our findings therefore provide important steps towards the study of, and intervention in, the SASP in human ageing and age-related disease.
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