Abstract Mycobacterium tuberculosis (MTB) infects 30% of all humans and kills someone every 20–30 s. Here we report genome-wide binding for ~80% predicted MTB transcription factors (TFs), assayed global expression following induction each TF. The DNA-binding network consists ~16,000 events from 154 TFs. We identify >50 TF-DNA consensus motifs >1,150 promoter-binding directly associated with proximal gene regulation. An additional ~4,200 are in promoter windows represent strong...

The resilience of Mycobacterium tuberculosis (MTB) is largely due to its ability effectively counteract and even take advantage the hostile environments a host. In order accelerate discovery characterization these adaptive mechanisms, we have mined compendium 2325 publicly available transcriptome profiles MTB decipher predictive, systems-scale gene regulatory network model. resulting modular organization 98% all genes within this was rigorously tested using two independently generated...

Article4 March 2019Open Access Transparent process Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation Eliza JR Peterson orcid.org/0000-0003-2934-5267 Institute Systems Biology, Seattle, WA, USA Search more papers by this author Rebeca Bailo orcid.org/0000-0003-3580-1273 School of Biosciences and Microbiology Infection, University Birmingham, UK Alissa C Rothchild orcid.org/0000-0001-7484-1193 Center Global Infectious Disease Research, Seattle...

The success of Mycobacterium tuberculosis (Mtb) is largely attributed to its ability physiologically adapt and withstand diverse localized stresses within host microenvironments. Here, we present a data-driven model (EGRIN 2.0) that captures the dynamic interplay environmental cues genome-encoded regulatory programs in Mtb. Analysis EGRIN 2.0 shows how modulation MtrAB two-component signaling system tunes Mtb growth response related microenvironmental cues. Disruption by tunable CRISPR...

Mycobacterium tuberculosis (MTB) is a pathogenic bacterium responsible for 12 million active cases of (TB) worldwide. The complexity and critical regulatory components MTB pathogenicity are still poorly understood despite extensive research efforts. In this study, we constructed the first systems-scale map transcription factor (TF) binding sites their target proteins in MTB. We FLAG-tagged overexpression constructs 206 TFs MTB, used ChIP-seq to identify genome-wide events surveyed global...

A non-tuberculous mycobacterium, Mycobacterium abscessus is an emerging opportunistic pathogen associated with difficult to treat pulmonary infections, particularly in patients suffering from cystic fibrosis. It capable of forming biofilms vitro that result increase already high levels antibiotic resistance this bacterium. Evidence M. forms biofilm-like microcolonies patient lungs and on medical devices further implicated the need investigate biofilm detail. Therefore, study we characterized...

Mycobacterium tuberculosis (MTB) displays the remarkable ability to transition in and out of dormancy, a hallmark pathogen's capacity evade immune system exploit susceptible individuals. Uncovering gene regulatory programs that underlie phenotypic shifts MTB during disease latency reactivation has posed challenge. We develop an experimental precisely control dissolved oxygen levels cultures order capture transcriptional events unfold as transitions into hypoxia-induced dormancy. Using...

The activities of the bacterial RecA protein are involved in de novo development and transmission antibiotic resistance genes, thus allowing bacteria to overcome metabolic stress induced by antibacterial agents. is ubiquitous highly conserved among bacteria, but has only distant homologs human cells. Together, this evidence points as a novel attractive drug target. All known functions require formation complex formed multiple adenosine 5'-O-triphosphate (ATP)-bound monomers on...

Mycobacterium tuberculosis (M. tuberculosis), the causative agent of human (TB), is estimated to be harbored by up 2 billion people in a latent TB infection (LTBI) state. The only vaccine approved for use humans, BCG, does not confer protection against establishment or reactivation from LTBI, so new candidates are needed specifically address this need. Following hypothesis that mycobacterial biofilms resemble aspects we modified BCG deleting BCG1419c gene create strain. In study, compared...

Mycobacterium tuberculosis and M. smegmatis form drug-tolerant biofilms through dedicated genetic programs. In support of a stepwise process regulating biofilm production in mycobacteria, it was shown elsewhere that lsr2 participates intercellular aggregation, while groEL1 required for maturation smegmatis. Here, by means RNA-Seq, we monitored the early steps bovis BCG, to distinguish aggregation from attachment surface. Genes encoding transcriptional regulators dosR BCG0114 (Rv0081) were...

is an environmental, non-tuberculous mycobacterial species, capable of causing infections in humans. Biofilm formation a key strategy used by

Mycobacterium tuberculosis (MTB) persists and survives antibiotic treatments by generating phenotypically heterogeneous drug-tolerant subpopulations. The surviving cells, persisters, are a major barrier to the relapse-free treatment of (TB), which is already killing >1.8 million people every year becoming deadlier with emergence multidrug-resistant strains.

Abstract We have previously reported the transcriptomic and lipidomic profile of first-generation, hygromycin-resistant (Hyg R ) version BCGΔBCG1419c vaccine candidate, under biofilm conditions. recently constructed characterized efficacy, safety, whole genome sequence, proteomic a second-generation BCGΔBCG1419c, strain lacking BCG1419c gene devoid antibiotic markers. Here, we compared antibiotic-less with BCG. assessed their colonial ultrastructural morphology, biofilm, c-di-GMP production...

The human commensal pathogen Streptococcus pneumoniae expresses a number of virulence factors that promote serious pneumococcal diseases, resulting in significant morbidity and mortality worldwide. These may give S. the capacity to escape immune defenses, resist antimicrobial agents, or combination both. Virulence also present possible points therapeutic intervention. activities surface endonuclease, EndA, allow establish invasive infection. EndA's role DNA uptake during transformation...

There is an urgent need for new drug regimens to rapidly cure tuberculosis. Here, we report the development of response assayer (DRonA) and "MLSynergy," algorithms perform rapid assays predict Mycobacterium tuberculosis (Mtb) combinations. Using a transcriptome signature cell viability, DRonA detects Mtb killing by diverse mechanisms in broth culture, macrophage infection, patient sputum, providing efficient more sensitive alternative time- resource-intensive bacteriologic assays. Further,...

The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states underlies its success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat infection (faster more completely), systems-level approach needed reveal complexity network-based adaptations Mtb. Here, we report predictive model...

has a lipid-rich cell envelope that is remodeled throughout infection to enable adaptation within the host. Few transcriptional regulators have been characterized coordinate synthesis of mycolic acids, major wall lipids mycobacteria. Here, we show acid desaturase regulator (MadR), repressor mycolate genes

B. histolyticus was first described by Weinberg and Seguin in 1915 as an obligate anaerobe from war wound infections which is may display a remarkable peculiar lytic activity. Pure virulent cultures injected intramuscularly into guinea pigs literally digest the flesh bones, hence name—histolyticus. Notwithstanding its marked ability to dissolve living muscular tissues proteolytic action brain, meat, milk, serum, egg mediums slow though fairly complete over long periods of time. found that...

Abstract The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies its success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat infection (faster more completely), systems-level approach needed reveal complexity network-based adaptations Mtb. Here, we report...

Mycobacterium tuberculosis (MTB) persists in the host for long periods, even during antibiotic treatment. Eliminating persister cells, which underlie this phenomenon and are primary reason treatment failure, is essential shortening TB regimen. Here, we report a novel methodology, Per-Sort that takes advantage of physiological characteristic (translational dormancy) persisters to isolate them without enrichment. Using Per-Sort, have discovered translationally dormant cells pre-exist as...