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Abstract Spectinamides are a novel class of antibiotics under development for the treatment of MDR- and XDR-tuberculosis, with 1599 and 1445 as early lead candidates within this group. In order to evaluate and differentiate the pharmacological properties of these compounds and assist in candidate selection and design of optimal dosing regimens in animal models of Mtb infection, time kill curve assessments were performed in a previously established in vitro PK/PD model system. The performed studies and subsequent pharmacometric analysis indicate that the anti-mycobacterial activity of 1599 exhibits concentration-dependent killing whereas 1445 shows time-dependent killing. These findings are supported by the fact that the PKPD index that best describes bacterial killing is T > MIC for 1445, but fC max /AUC for 1599. The differential killing behavior among the lead candidates can be rationalized by the differences in post-antibiotic effect: 15.7 h for 1445 compared the 133 h for 1599. Overall, the PK/PD based analysis of the in vitro pharmacologic killing profile of spectinamides 1599 and 1445 on mycobacteria provided valuable insights that contributed to lead candidate selection and preclinical development of these compounds. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The main challenge for vaccine development or improvement is the lack of safe adjuvants or immunostimulants that induce protective immune responses and can be used for mucosal immunization, which is a highly desirable strategy for vaccination against infectious diseases acquired by oral or intranasal routes. One promising alternative is the use of biodegradable and biocompatible polymeric microparticles. Recently, we developed an immobilization and delivery system with starch microparticles (SMPs) and a starch-binding domain (SBD tag ) suitable for the mucosal administration of antigens and the induction of antigen-specific immune responses. Here, we explore the immunostimulant and reinforcing potential of the system using BALB/c mice with progressive pulmonary tuberculosis (PPT). The heat shock protein alpha-crystallin from Mycobacterium tuberculosis immobilized on SMPs (µAcr-SBD tag ) or SMPs alone were administered nasally as boosters to BCG-vaccinated mice without any extra adjuvant. The mice were challenged intratracheally with either moderately virulent or highly virulent M. tuberculosis strains. Our results showed that the administration of either the immobilized antigen or SMPs as a booster for the BCG vaccination induced a significant reduction of bacterial loads in the lungs of mice, even more than in mice that received the BCG vaccination alone. Since no difference was observed in pulmonary bacillary burdens between the two reinforced groups, the obtained effect was most likely primarily caused by the starch. As determined by histological study, the administration of boosters did not contribute to the progress of pneumonia, which diminishes the safety concerns related to the administration of SMPs intranasally. Taken together, our findings suggest that this system may be considered as a new carbohydrate-based adjuvant suitable for mucosal vaccines against tuberculosis and other infectious diseases, and more generally, they highlight the potential of particulate α-glucans as immune response modifiers. [ABSTRACT FROM AUTHOR]

The tuberculosis vaccine BCG Δ ureC :: hly is the most advanced BCG replacement candidate in phase II clinical development. Here we assess the protective capacity of the construct administered to mice as homologous prime-boost vaccine prior Mycobacterium tuberculosis infection and as post-exposure vaccine. Multiple immunization did not improve the superior protection of BCG Δ ureC :: hly over BCG. Animals with subclinical tuberculosis were better protected when vaccinated with BCG Δ ureC :: hly as compared to BCG. Our findings suggest further consideration of BCG Δ ureC :: hly as post-exposure vaccine. [ABSTRACT FROM AUTHOR]

Abstract: In this review, published peer-reviewed preclinical studies using prime-boost tuberculosis (TB) vaccine regimens in animal challenge models for tuberculosis have been evaluated. These studies have been divided into groups that describe prime-boost vaccine combinations that performed better than, equivalent to, or worse than the currently used BCG vaccine. Review of the data has revealed interesting findings, including that more than half of the published studies using BCG as a prime combined with a novel boost vaccine give better efficacy than BCG alone and that the greatest reduction in Mycobacterium tuberculosis (M.tb.) colonization of animal tissues is provided by viral vectored vaccines delivered intranasally. Careful evaluation of these data should assist in defining the value of prime-boost regimens for advancement into human TB vaccine trials and stimulate the development of criteria for choosing which vaccine candidates should be studied further. [Copyright &y& Elsevier]

Abstract: In vitro, Toll-like receptors (TLR)2, 4 and 9 as well as NOD-like receptor 2 critically determine macrophage responses to Mycobacterium tuberculosis (Mtb) infection. However, in low-dose experimental murine tuberculosis, single or multiple deficiencies in TLRs 2, 4, 9 or NOD2 have little, if any, impact on early mycobacterial growth containment, granuloma formation and survival. Here, we analyzed the relevance of NALP3, one component of the danger-signaling inflammasome, for (i) Mtb-induced cytokine secretion in vitro and in vivo, (ii) restriction of Mtb replication in infected organs and (iii) granuloma formation. In the absence of functional NALP3, there was no IL-1β and IL-18 production in Mtb-infected dendritic cells and macrophages in vitro, whereas secretion of IL-1α, IL-12p40 and TNF remained unaffected. After three weeks of infection, NALP3-deficient as well as IL-18-deficient mice were as capable as wildtype mice of restricting Mtb loads at a plateau level within well-differentiated granulomas. In conclusion, despite its involvement in cytokine processing, NALP3 is not essential for induction of protective immunity to Mtb. [ABSTRACT FROM AUTHOR]

Summary: The guinea pig is a very useful animal model for evaluating new tuberculosis candidate vaccines. In addition to established methods for bacterial load determinations, new technologies are emerging that allow us to specifically evaluate effects of vaccines on the pathology of the disease process and the expression by the host of cell mediated immunity. Limitations to the model include housing and related costs, which often contribute to issue with study design and adequate statistical power, and the use of laboratory strains of Mycobacterium tuberculosis which lack the high virulence and immune evasion properties of newly emerging clinical isolates. [Copyright &y& Elsevier]

Abstract: In order to determine the relative importance of fucosyltransferase (Fuc-T)-directed functionalization of selectin ligands for chronic inflammatory and antibacterially protective responses in vivo, mice selectively deficient for Fuc-TIV, Fuc-TVII or both were infected by aerosol with Mycobacterium tuberculosis H37Rv. Fuc-TIV/Fuc-TVII-deficient, and to a lesser extent, Fuc-TVII-deficient mice succumbed significantly faster to infection than Fuc-TIV-deficient and wildtype (WT) mice, although no differentially increased bacterial load or qualitatively different histopathology was apparent in moribund mice. To determine if the cause of accelerated death was associated with defective induction of immune responses in the lung due to the diminished T cell content in the mediastinal lymph nodes of Fuc-T-deficient mice, intravenous infection in WT or double-deficient mice was performed. Again, Fuc-TIV/Fuc-TVII mice succumbed significantly faster than WT mice. To determine whether the early demise of Fuc-TIV/Fuc-TVII-deficient mice was due to accelerated tissue pathology, a mouse model of mycobacteria-induced granuloma necrosis was used. There was no difference in the kinetics and quality of caseation induced by Mycobacterium avium TMC724 in all mouse strains investigated. Together, our data show that a deficiency in Fuc-TVII, and in a more pronounced fashion, a combined deficiency in both Fuc-TIV and Fuc-TVII, leads to accelerated death following M. tuberculosis infection that is neither caused by increased bacterial proliferation nor by discernibly gross differences in tissue pathology. These results suggest that targeting selectin ligand function during treatment of chronic inflammatory disorders may run the risk of accelerating TB disease progression. [Copyright &y& Elsevier]

Summary: To control tuberculosis in the world today an additional approach would be most welcomed. Preventing (or reducing) pulmonary cavity formation is one such approach that has been almost completely neglected. Pulmonary cavity formation and the extracellular growth of tubercle bacilli in cavities cause bronchial spread of the disease in adult patients and spread of the bacillus to the environment where they infect other people. Therefore, cavity formation perpetuates tuberculosis in mankind. If no cavities form, the patient is much less infectious. Also, cavity formation often allows the tubercle bacillus to multiply (extracellularly) to tremendous numbers. Therefore, in humans almost all multidrug-resistant tubercle bacilli develop in cavities. This communication reviews the literature on liquefaction and cavity formation, and lists some of the responsible hydrolytic enzymes. It also describes a simple method to identify inhibitory pharmaceuticals, i.e., to observe their effect on the liquefaction and ulceration of skin lesions produced in rabbits by ascending concentrations of live or dead tubercle bacilli. [Copyright &y& Elsevier]