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      Atorvastatin Potentially Reduces Mycobacterial Severity through Its Action on Lipoarabinomannan and Drug Permeability in Granulomas

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          ABSTRACT

          The majority of preclinical research has shown that Mycobacterium tuberculosis can modify host lipids in various ways. To boost its intramacrophage survival, M. tuberculosis causes host lipids to build up, resulting in the development of lipid-laden foam cells. M. tuberculosis binds to and enters the macrophage via the cell membrane cholesterol. Aggregation of cholesterol in the cell wall of M. tuberculosis and an increase in vascularity at the granuloma site reduce the permeability of rifampicin and isoniazid concentrations. However, very few studies have assessed the effect of statins on drug penetration. Here, we used atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to observe its effect on the bacterial burden by increasing the drug concentration at the infection site. We looked into how atorvastatin could be used in conjunction with first-line drugs to promote drug permeation. In this study, we detected an accumulation of drugs at the peripheral sites of the lungs and impaired drug distribution to the diseased sites. The efficacy of antituberculosis drugs, with atorvastatin as an adjunct, on the viability of M. tuberculosis cells was demonstrated. A nontoxic statin dosage established phenotypic and normal granuloma vasculature and showed an additive effect with rifampicin and isoniazid. Our data show that statins help to reduce the tuberculosis bacterial burden. Our findings reveal that the bacterial load is connected with impaired drug permeability resulting from lipid accumulation in the bacterial cell wall. Statin therapy combined with antituberculosis medications have the potential to improve treatment in tuberculosis patients.

          IMPORTANCE Mycobacterium tuberculosis binds to and enters the macrophage via the cell membrane cholesterol. M. tuberculosis limits phagosomal maturation and activation without engaging in phagocytosis. Aggregation of cholesterol in the cell wall of M. tuberculosis and an increase in the vascularity at the granuloma site reduce the permeability of rifampicin and isoniazid concentrations. However, very few studies have assessed the effect of statins on drug penetration, which can be increased through a reduction in cholesterol and vascularity. Herein, we used atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to observe its effect on bacterial burden through increasing the drug concentration at the infection site. Our main research goal is to diminish mycobacterial dissemination and attenuate bacterial growth by increasing drug permeability.

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          Molecular basis of bacterial outer membrane permeability revisited.

          Gram-negative bacteria characteristically are surrounded by an additional membrane layer, the outer membrane. Although outer membrane components often play important roles in the interaction of symbiotic or pathogenic bacteria with their host organisms, the major role of this membrane must usually be to serve as a permeability barrier to prevent the entry of noxious compounds and at the same time to allow the influx of nutrient molecules. This review summarizes the development in the field since our previous review (H. Nikaido and M. Vaara, Microbiol. Rev. 49:1-32, 1985) was published. With the discovery of protein channels, structural knowledge enables us to understand in molecular detail how porins, specific channels, TonB-linked receptors, and other proteins function. We are now beginning to see how the export of large proteins occurs across the outer membrane. With our knowledge of the lipopolysaccharide-phospholipid asymmetric bilayer of the outer membrane, we are finally beginning to understand how this bilayer can retard the entry of lipophilic compounds, owing to our increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopolysaccharide structure is modified by environmental conditions.
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            How to calculate sample size in animal studies?

            Calculation of sample size is one of the important component of design of any research including animal studies. If a researcher select less number of animals it may lead to missing of any significant difference even if it exist in population and if more number of animals selected then it may lead to unnecessary wastage of resources and may lead to ethical issues. In this article, on the basis of review of literature done by us we suggested few methods of sample size calculations for animal studies.
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              Extrapulmonary tuberculosis: an overview.

              In the 1980s, after a steady decline during preceding decades, there was a resurgence in the rate of tuberculosis in the United States that coincided with the acquired immunodeficiency syndrome epidemic. Disease patterns since have changed, with a higher incidence of disseminated and extrapulmonary disease now found. Extrapulmonary sites of infection commonly include lymph nodes, pleura, and osteoarticular areas, although any organ can be involved. The diagnosis of extrapulmonary tuberculosis can be elusive, necessitating a high index of suspicion. Physicians should obtain a thorough history focusing on risk behaviors for human immunodeficiency virus (HIV) infection and tuberculosis. Antituberculous therapy can minimize morbidity and mortality but may need to be initiated empirically. A negative smear for acid-fast bacillus, a lack of granulomas on histopathology, and failure to culture Mycobacterium tuberculosis do not exclude the diagnosis. Novel diagnostic modalities such as adenosine deaminase levels and polymerase chain reaction can be useful in certain forms of extrapulmonary tuberculosis. In general, the same regimens are used to treat pulmonary and extrapulmonary tuberculosis, and responses to antituberculous therapy are similar in patients with HIV infection and in those without. Treatment duration may need to be extended for central nervous system and skeletal tuberculosis, depending on drug resistance, and in patients who have a delayed or incomplete response. Adjunctive corticosteroids may be beneficial in patients with tuberculous meningitis, tuberculous pericarditis, or miliary tuberculosis with refractory hypoxemia.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                Microbiol Spectr
                Microbiol Spectr
                spectrum
                Microbiology Spectrum
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2165-0497
                31 January 2023
                Mar-Apr 2023
                31 January 2023
                : 11
                : 2
                : e03197-22
                Affiliations
                [a ] Department of Microbiology and Molecular Biology, ICMR, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, India
                [b ] Division of Pharmaceutics and Pharmacokinetics, CSIR, Central Drug Research Institute, Lucknow, India
                [c ] Department of Biotechnology, GLA University, Mathura, India
                Institut Pasteur
                Author notes

                The authors declare no conflict of interest.

                Author information
                https://orcid.org/0000-0001-6519-3200
                Article
                03197-22 spectrum.03197-22
                10.1128/spectrum.03197-22
                10100658
                36719189
                48c4f1b7-3795-4099-abe9-643426445b0c
                Copyright © 2023 Davuluri et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 14 August 2022
                : 5 November 2022
                Page count
                supplementary-material: 0, Figures: 5, Tables: 1, Equations: 0, References: 54, Pages: 11, Words: 7947
                Funding
                Funded by: Department of Science and Technology, Government of Kerala (Department of Science and Technology), FundRef https://doi.org/10.13039/501100006143;
                Award ID: IF180175
                Award Recipient :
                Categories
                Research Article
                antimicrobial-chemotherapy, Antimicrobial Chemotherapy
                Custom metadata
                March/April 2023

                chemokines,drug distribution,statins,vasculature,tuberculosis,atorvastatin,drug penetration,mycobacterium tuberculosis,granuloma

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