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Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB. [ABSTRACT FROM AUTHOR]

Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-β, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP-mediated IFN-β induction during M. tuberculosis infection requires stimulator of interferon genes (STING)-signaling. We observed that c-di-AMP induction of IFN-β is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), but cGAS nevertheless contributes substantially to the overall IFN-β response to M. tuberculosis infection. In sum, our results reveal c-di-AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis. [ABSTRACT FROM AUTHOR]

Over 30% of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet only ∼5-10% will develop clinical disease. Despite considerable effort, researchers understand little about what distinguishes individuals whose infection progresses to active tuberculosis (TB) from those whose infection remains latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb. Active disease occurs in ∼45% of infected macaques and is defined by clinical, microbiologic and immunologic signs, whereas the remaining infected animals are clinically asymptomatic. Here, we use individually marked Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lung lesions are probably founded by a single bacterium and reach similar maximum burdens. Despite this observation, the fate of individual lesions varies substantially within the same host. Notably, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting that critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be useful in developing effective interventions to prevent active TB. [ABSTRACT FROM AUTHOR]

We report the involvement of an evolutionarily conserved set of mycobacterial genes, the esx-3 region, in evasion of bacterial killing by innate immunity. Whereas high-dose intravenous infections of mice with the rapidly growing mycobacterial species Mycobacterium smegmatis bearing an intact esx-3 locus were rapidly lethal, infection with an M. smegmatis ?esx-3 mutant (here designated as the IKE strain) was controlled and cleared by a MyD88-dependent bactericidal immune response. Introduction of the orthologous Mycobacterium tuberculosis esx-3 genes into the IKE strain resulted in a strain, designated IKEPLUS, that remained susceptible to innate immune killing and was highly attenuated in mice but had a marked ability to stimulate bactericidal immunity against challenge with virulent M. tuberculosis. Analysis of these adaptive immune responses indicated that the highly protective bactericidal immunity elicited by IKEPLUS was dependent on CD4+ memory T cells and involved a distinct shift in the pattern of cytokine responses by CD4+ cells. Our results establish a role for the esx-3 locus in promoting mycobacterial virulence and also identify the IKE strain as a potentially powerful candidate vaccine vector for eliciting protective immunity to M. tuberculosis. [ABSTRACT FROM AUTHOR]

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-? (IFN-?), tumor necrosis factor-? (TNF-?) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-? Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-? Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease. [ABSTRACT FROM AUTHOR]

The peptidoglycan layer is a vital component of the bacterial cell wall. The existing paradigm describes the peptidoglycan network as a static structure that is cross-linked predominantly by 4→3 transpeptide linkages. However, the nonclassical 3→3 linkages predominate the transpeptide networking of the peptidoglycan layer of nonreplicating Mycobacterium tuberculosis. The molecular basis of these linkages and their role in the physiology of the peptidoglycan layer, virulence and susceptibility of M. tuberculosis to drugs remain undefined. Here we identify MT2594 as an L,D-transpeptidase that generates 3→3 linkages in M. tuberculosis. We show that the loss of this protein leads to altered colony morphology, loss of virulence and increased susceptibility to amoxicillin-clavulanate during the chronic phase of infection. This suggests that 3→3 cross-linking is vital to the physiology of the peptidoglycan layer. Although a functional homolog exists, expression of ldtMt2 is dominant throughout the growth phases of M. tuberculosis. 4→3 transpeptide linkages are targeted by one of the most widely used classes of antibacterial drugs in human clinical use today, β-lactams. Recently, meropenem-clavulanate was shown to be effective against drug-resistant M. tuberculosis. Our study suggests that a combination of L,D-transpeptidase and β-lactamase inhibitors could effectively target persisting bacilli during the chronic phase of tuberculosis. [ABSTRACT FROM AUTHOR]

Few tools exist to assess replication of chronic pathogens during infection. This has been a considerable barrier to understanding latent tuberculosis, and efforts to develop new therapies generally assume that the bacteria are very slowly replicating or nonreplicating during latency. To monitor Mycobacterium tuberculosis replication within hosts, we exploit an unstable plasmid that is lost at a steady, quantifiable rate from dividing cells in the absence of antibiotic selection. By applying a mathematical model, we calculate bacterial growth and death rates during infection of mice. We show that during chronic infection, the cumulative bacterial burden—enumerating total live, dead and removed organisms encountered by the mouse lung—is substantially higher than estimates from colony-forming units. Our data show that M. tuberculosis replicates throughout the course of chronic infection of mice and is restrained by the host immune system. This approach may also shed light on the replication dynamics of other chronic pathogens. [ABSTRACT FROM AUTHOR]

Acidification of the phagosome is considered to be a major mechanism used by macrophages against bacteria, including Mycobacterium tuberculosis (Mtb). Mtb blocks phagosome acidification, but interferon-γ (IFN-γ) restores acidification and confers antimycobacterial activity. Nonetheless, it remains unclear whether acid kills Mtb, whether the intrabacterial pH of any pathogen falls when it is in the phagosome and whether acid resistance is required for mycobacterial virulence. In vitro at pH 4.5, Mtb survived in a simple buffer and maintained intrabacterial pH. Therefore, Mtb resists phagolysosomal concentrations of acid. Mtb also maintained its intrabacterial pH and survived when phagocytosed by IFN-γ–activated macrophages. We used transposon mutagenesis to identify genes responsible for Mtb's acid resistance. A strain disrupted in Rv3671c, a previously uncharacterized gene encoding a membrane-associated protein, was sensitive to acid and failed to maintain intrabacterial pH in acid in vitro and in activated macrophages. Growth of the mutant was also severely attenuated in mice. Thus, Mtb is able to resist acid, owing in large part to Rv3671c, and this resistance is essential for virulence. Disruption of Mtb's acid resistance and intrabacterial pH maintenance systems is an attractive target for chemotherapy. [ABSTRACT FROM AUTHOR]

The success of Mycobacterium tuberculosis (Mtb) as a human pathogen relies on its ability to resist eradication by the immune system. The identification of mechanisms that enable Mtb to persist is key for finding ways to limit latent tuberculosis, which affects one-third of the world's population. Here we show that conditional gene silencing can be used to determine whether an Mtb gene required for optimal growth in vitro is also important for virulence and, if so, during which phase of an infection it is required. Application of this approach to the prcBA genes, which encode the core of the mycobacterial proteasome, revealed an unpredicted requirement of the core proteasome for the persistence of Mtb during the chronic phase of infection in mice. Proteasome depletion also attenuated Mtb in interferon-γ–deficient mice, pointing to a function of the proteasome beyond defense against the adaptive immune response. Genes that are essential for growth in vitro, in vivo or both account for approximately 20% of Mtb's genome. Conditional gene silencing could therefore facilitate the validation of up to 800 potential Mtb drug targets and improve our understanding of host-pathogen dynamics. [ABSTRACT FROM AUTHOR]

Genes involved in fatty acid catabolism have undergone extensive duplication in the genus Mycobacterium, which includes the etiologic agents of leprosy and tuberculosis. Here, we show that prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis. Although deletion of icl1 or icl2, the genes that encode ICL1 and ICL2, respectively, had little effect on bacterial growth in macrophages and mice, deletion of both genes resulted in complete impairment of intracellular replication and rapid elimination from the lungs. The feasibility of targeting ICL1 and ICL2 for chemical inhibition was shown using a dual-specific ICL inhibitor, which blocked growth of M. tuberculosis on fatty acids and in macrophages. The absence of ICL orthologs in mammals should facilitate the development of glyoxylate cycle inhibitors as new drugs for the treatment of tuberculosis. [ABSTRACT FROM AUTHOR]

Protective immunity against Mycobacterium tuberculosis depends on the generation of a TH1-type cellular immune response, characterized by the secretion of interferon-?(IFN-?) from antigen-specific T cells. The induction of potent cellular immune responses by vaccination in humans has proven difficult. Recombinant viral vectors, especially poxviruses and adenoviruses, are particularly effective at boosting previously primed CD4+ and CD8+ T-cell responses against a number of intracellular pathogens in animal studies. In the first phase 1 study of any candidate subunit vaccine against tuberculosis, recombinant modified vaccinia virus Ankara (MVA) expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-?-secreting T cells when used alone in bacille Calmette-Guérin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-?-secreting T cells were induced, and at 24 weeks after vaccination these levels were 5-30 times greater than in vaccinees administered a single BCG vaccination. Boosting vaccinations with MVA85A could offer a practical and efficient strategy for enhancing and prolonging antimycobacterial immunity in tuberculosis-endemic areas. [ABSTRACT FROM AUTHOR]

'Hot zones' are areas that have>5% prevalence (or incidence) of multidrug-resistant tuberculosis (MDRTB). We present a new mathematical model (the amplifier model) that tracks the emergence and evolution of multiple (pre-MDR, MDR and post-MDR) strains of drug-resistant Mycobacterium tuberculosis. We reconstruct possible evolutionary trajectories that generated hot zones over the past three decades, and identify the key causal factors. Results are consistent with recently reported World Health Organization (WHO) data. Our analyses yield three important insights. First, paradoxically we found that areas with programs that successfully reduced wild-type pansensitive strains often evolved into hot zones. Second, some hot zones emerged even when MDR strains were substantially less fit (and thus less transmissible) than wild-type pansensitive strains. Third, levels of MDR are driven by case-finding rates, cure rates and amplification probabilities. To effectively control MDRTB in the hot zones, it is essential that the WHO specify a goal for minimizing the amplification probability. [ABSTRACT FROM AUTHOR]

Mathematical models have recently been used to predict the future burden of multidrug-resistant tuberculosis (MDRTB). These models suggest the threat of multidrug resistance to TB control will depend on the relative 'fitness' of MDR strains and imply that if the average fitness of MDR strains is considerably less than that of drug-sensitive strains, the emergence of resistance will not jeopardize the success of tuberculosis control efforts. Multidrug resistance in M. tuberculosis is conferred by the sequential acquisition of a number of different single-locus mutations that have been shown to have heterogeneous phenotypic effects. Here we model the impact of initial fitness estimates on the emergence of MDRTB assuming that the relative fitness of MDR strains is heterogeneous. We find that even when the average relative fitness of MDR strains is low and a well-functioning control program is in place, a small subpopulation of a relatively fit MDR strain may eventually outcompete both the drug-sensitive strains and the less fit MDR strains. These results imply that current epidemiological measures and short-term trends in the burden of MDRTB do not provide evidence that MDRTB strains can be contained in the absence of specific efforts to limit transmission from those with MDR disease. [ABSTRACT FROM AUTHOR]

Protective immunity against Mycobacterium tuberculosis involves major histocompatibility complex class I (MHC-I)- and CD1-restricted CD8 T cells, but the mechanisms underlying antigen delivery to antigen-presenting molecules remain enigmatic. Macrophages, the primary host cells for mycobacteria, are CD1-negative. Here we show that M. tuberculosis phagosomes are secluded from the cytosolic MHC-I processing pathway and that mycobacteria-infected cells lose their antigen-presenting capacity. We also show that mycobacteria induce apoptosis in macrophages, causing the release of apoptotic vesicles that carry mycobacterial antigens to uninfected antigen-presenting cells (APCs). Inhibition of apoptosis reduced transfer of antigens to bystander cells and activation of CD8 T cells. Uninfected dendritic cells, which engulfed extracellular vesicles, were indispensable for subsequent cross-presentation of antigens, through MHC-I and CD1b, to T cells from mycobacteria-sensitized donors. This new 'detour' pathway for presentation of antigens from a phagosome-contained pathogen shows the functional significance of infection-induced apoptosis in the activation of CD8 T cells specific for both protein and glycolipid antigens in tuberculosis. [ABSTRACT FROM AUTHOR]

With the advent of HIV and the widespread emergence of drugresistant strains of Mycobacterium tuberculosis, newer control strategies in the form of a better vaccine could decrease the global incidence of tuberculosis. A desirable trait in an effective live attenuated vaccine strain is an ability to persist within the host in a limited fashion in order to produce important protective antigens in vivo. Attenuated M. tuberculosis vaccine candidates have been constructed by deleting genes required for growth in mice. These candidate vaccines did not elicit adequate protective immunity in animal models, due to their inability to persist sufficiently long within the host tissues. Here we report that an auxotrophic mutant of M. tuberculosis defective in the de novo biosynthesis of pantothenic acid (vitamin B5) is highly attenuated in immunocompromised SCID mice and in immunocompetent BALB/c mice. SCID mice infected with the pantothenate auxotroph survived significantly longer (250 days) than mice infected with either bacille Calmette-Guerin (BCG) vaccine or virulent M. tuberculosis (77 and 35 days, respectively). Subcutaneous immunization with this auxotroph conferred protection in C57BL/6J mice against an aerosol challenge with virulent M. tuberculosis, which was comparable with that afforded by BCG vaccination. Our findings highlight the importance of de novo pantothenate biosynthesis in limiting the intracellular survival and pathogenesis of M. tuberculosis without reducing its immunogenicity in vaccinated mice. [ABSTRACT FROM AUTHOR]

Elevated expression of heat-shock proteins (HSPs) can benefit a microbial pathogen struggling to penetrate host defenses during infection, but at the same time might provide a crucial signal alerting the host immune system to its presence. To determine which of these effects predominate, we constructed a mutant strain of Mycobacterium tuberculosis that constitutively overexpresses Hsp70 proteins. Although the mutant was fully virulent in the initial stage of infection, it was significantly impaired in its ability to persist during the subsequent chronic phase. Induction of microbial genes encoding HSPs might provide a novel strategy to boost the immune response of individuals with latent tuberculosis infection. [ABSTRACT FROM AUTHOR]

Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis. [ABSTRACT FROM AUTHOR]

The article investigates the mechanisms used by Mycobacterium tuberculosis to survive within the host macrophage. Persistence of M. tuberculosis in humans depends on its ability to survive within the host macrophage. Macrophages are phagocytes at the frontline of host immune defense against microbial pathogens. To prevent its death, the bacterium must resist antimicrobial mechanisms or subvert macrophage signaling pathways. Evidence suggests that the two strategies are not mutually exclusive.

The article investigates Mycobacterium tuberculosis persistence despite the availability of drugs that than can stably cure it by researchers from Baltimore, Maryland. Identification of drug targets in M. tuberculosis has been a challenge for researchers. However, high-throughput mutagenesis with transposons together with microarray-based genome and transcriptome profiling has begun to meet this challenge.

Isoniazid is one of the most effective antituberculosis drugs, yet its precise mechanism of action is still controversial. Using specialized linkage transduction, a single point mutation allele (S94A) within the putative target gene inhA was transferred in Mycobacterium tuberculosis. The inhA(S94A) allele was sufficient to confer clinically relevant levels of resistance to isoniazid killing and inhibition of mycolic acid biosynthesis. This resistance correlated with the decreased binding of the INH-NAD inhibitor to InhA, as shown by enzymatic and X-ray crystallographic analyses, and establishes InhA as the primary target of isoniazid action in M. tuberculosis. [ABSTRACT FROM AUTHOR]

Focuses on perspspective of the identification of the genome sequence of Mycobacterium tuberculosis along with genetic tools for post-genomic research on tuberculosis. Evolution of comparative genomics; Research on in vivo phenotypes.

Mycobacterium tuberculosis is a globally successful pathogen due to its ability to persist for long periods of time unrecognized by the human immune system. The panoply of genes that allows the organism to enter latency and then re-emerge later during endogenous reinfection are now being elucidated. Novel antimicrobials and vaccines will need to target these mycobacterial pathogenic mechanisms to suceed against tuberculosis. [ABSTRACT FROM AUTHOR]

DNA vaccines may be useful in overcoming persistent tuberculosis infections [ABSTRACT FROM AUTHOR]

The article focuses on the study by K. A. Sweeney and colleagues regarding the improved vaccine for the treatment of Mycobacterium tuberculosis. It states that a recombinant strain of Mycobacterium smegmatis wherein the ESX-3 secretion system was substituted with orthologous ESX-3 secretion system from M. tuberculosis is effective in protecting mice. It says that knowing the invasion of the disease in immune killing and genes will lead the rationale for vaccine design of mycobacterial strains.

The article offers updates on medical research studies. It notes that the metabolites of phosphatidylcholine, a dietary lipid have been associated to the risk for cardiovascular disorders. It mentions that macrophage infection by Mycobacterium species contributes to the development of a duplicating and metabolically active population of intracellular bacteria that are multidrug tolerant. It also cites the unexpected role of eosinophils in regulating glucose homeostasis.

The article focuses on the study which suggests that Mycobacterium tuberculosis can tolerate the proton-rich environment generated within macrophages activated by a cytokine that is released during infection. The study examined survival of virulent M. tuberculosis in simple rather than complex growth medium to exclude detergent- and albumin-associated artifacts over a range of pH values. It shows that regulation of bacterial periplasmic pH was essential for infection within an intact host.

The article reports on the development of drugs to treat tuberculosis and other bacterial diseases. While microbial populations have been steadily accumulating drug resistance traits, there has been little interest in developing new antibacterial drugs. In fact, most antibiotics currently available are merely derivatives of old compounds. However, as reflected in research studies, many advancements are finally being harnessed to find more effective treatments for tuberculosis.

The article highlights various research undertakings on tuberculosis. From an evolutionary perspective, Mycobacterium tuberculosis and its close relatives are so similar that they seem to have separated from a common ancestor only 20,000-35,000 years ago. M. tuberculosis contains diverse lipids in its cell envelope, all with nonredundant roles in virulence or in persistence of infection. It effectively avoids immune response and persist in the host by reinfecting the host outside granulomas.

The article investigates the virulence and specialized secretions of Mycobacterium tuberculosis. The genomic region lost during the attenuation of Bacillus Calmette-Guérin (BCG) vaccine encodes a newly discovered secretion system conserved among gram-positive bacteria. Several studies have dissected the components of this system, thereby revealing a unique M. tuberculosis-specific signals for export of bacterial proteins into the host.

The article examines the role of pathogen-derived lipids on the virulence of Mycobactrium tuberculosis by researchers from New York City. During infections, M. tuberculosis has to acquire nutrients and resist host defense. The pathogen achieves this by using host-derived lipids as food, while pathogen-derived lipids mediate immune suppression.

The article reports that mycobacterium tuberculosis adapts to the low-glucose conditions in its host by using lipids as a fuel source. The requirements for mycobacterium tuberculosis survival in vivo have been defined largely by studying mutants that grow well in vitro which then show diminished ability to grow in macrophages or during infection of a mouse. During in vitro growth, mycobacterium tuberculosis rapidly metabolizes glucose and glycerol from the medium. These substrates provide both an efficient source of energy as well as convenient biosynthetic building blocks.

Focuses on the structure of the microorganism Mycobacterium tuberculosis (M. tuberculosis). Revelation of relatively little information on the environmental condition that M. tuberculosis encounters within the phagosome; Discussion of how M. tuberculosis deals with stress; Examination of the mechanism that restricts nutrient availability within the phagosome.

Discusses studies focusing on the colonization of extrapulmonary sites by the Mycobacterium tuberculosis (TB). Prevalence of the TB bacterium in the human population; Role and relevance of extrapulmonary infection by the TB agent.

The article offers information related to the announcement of the U.S. National Institute of General Medical Sciences (NIGMS) to wind down the Protein Structure Initiative (PSI), a program of worth 885 million dollar that spawned the Tuberculosis Structural Genomics Consortium (TBSGC) research. It informs that the PSI was designed to crack the structure of MmpL3, a protein encoded by Mycobacterium tuberculosis.

The article reports on a study which investigates the growth and division of mycobacterium populations and its implications for the application of antibiotic treatments to eliminate infection in tuberculosis.

The article reports on the concern of scientists regarding the emergence of extensively drug-resistant (XDR) strain of Mycobacterium tuberculosis. XDR tuberculosis (XDR-TB) is a strain that does not respond to the standard drug treatment and have appeared in virtually all countries. XDR-TB occurs when resistance to second-line drugs develops. It is extremely difficult to treat and cases have been confirmed worldwide.

Presents a clinical trial for the new vaccine on the global effort to eradicate tuberculosis (TB) in the U.S. Critical element in the fight against TB; Major secretory protein of mycobacterium tuberculosis; Evaluation on the route of administration.

Discusses the correlation between the virulence of Mycobacterium tuberculosis and the formation of braided microscopic bundles. Structure of bacterial colony; Lack of cell surface mutants.