Enhanced susceptibility of multidrug resistant strains of Mycobacterium tuberculosis to granulysin peptides correlates with a reduced fitness phenotype

Toro, Juan Carlos; Hoffner, Sven; Linde, Charlotte; Andersson, Mats; Andersson, Jan; Grundström, Susanna

doi:10.1016/j.micinf.2006.02.030

Cited by 26 publications

(16 citation statements)

References 30 publications

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“…To hypothesize on the reasons, it is crucial to report the results of Swedish study investigating the different susceptibility to natural immunity of susceptible versus resistant M. tuberculosis strains, and the growth rate of each strain. The results suggest that resistant mutants are likely to be more prone to natural immune defense mechanisms than drug-susceptible ones, even if the host immune system is compromised 17. In addition, the commonly distributed type of strain into the community can also explain this finding.…”

Section: Discussionmentioning

confidence: 89%

Determinants of multidrug-resistant tuberculosis in Addis Ababa, Ethiopia

Assefa¹,

Seyoum

Oljira

2017

IDR

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Multidrug-resistant tuberculosis (MDR-TB) has been jeopardizing the global effort to prevent and control tuberculosis (TB). However, data on MDR-TB in Ethiopia in general, and in our study area in particular, are very scarce. The aim of this study was to identify determinants of MDR-TB in a cohort of patients managed in two referral hospitals of Addis Ababa, Ethiopia, between April 1, 2013 and June 30, 2013. A health facility-based case–control study was conducted. A total of 710 TB patients (229 confirmed MDR-TB and 481 drug susceptible TB patients) were enrolled in this study. Identified independent determinants for MDR-TB were contact history with a known TB patient (adjusted odds ratio [AOR]: 1.9, 95% CI: 1.1–3.3), previous history of TB treatment (AOR: 11.9, 95% CI: 6.8–21), history of hospitalization (AOR: 4.4 95% CI: 2.2–7.8), sputum-smear positivity (AOR: 1.9, 95% CI: 1.1–3.4), and social stigma (AOR: 5.1, 95% CI: 1.8–14.4). These identified factors should be considered for use in MDR-TB screening tool development if universal drug susceptibility testing is not possible. Moreover, TB infection control practices in health care settings should be further strengthened. As factors may vary from region to region, further broader studies need to be conducted in other parts of Ethiopia.

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Section: Discussionmentioning

confidence: 89%

Determinants of multidrug-resistant tuberculosis in Addis Ababa, Ethiopia

Assefa¹,

Seyoum

Oljira

2017

IDR

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“…4 Granulysin is also able to generate pores on the surface of bacteria, promoting infiltration of the granzymes into the bacterial cytosol and killing various bacteria via the generation of radical oxygen species (ROS). 7 In particular, synthetic peptides based on granulysin also exhibit better inhibition activity to single drug-resistant and even MDR-TB strains in vitro, 8 and in transgenic mice that constitutively express human granulysin, there is significantly inhibition of the growth of M. tuberculosis in infected mice. 9 However, to kill intracellular M. tuberculosis, granulysin depends on the effect of perforin to cross the cell membrane of host cells.…”

Section: Introductionmentioning

confidence: 99%

Inhalation of recombinant adenovirus expressing granulysin protects mice infected with Mycobacterium tuberculosis

Huang

et al. 2015

Gene Ther

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Granulysin is a cytolytic molecule with perforin and granzymes that is expressed by activated human CTLs, NK and γδ T cells, and it has broad antimicrobial activity, including to drug-sensitive and drug-resistant Mycobacterium tuberculosis. We hypothesized that approaches facilitating the expression of granulysin in M. tuberculosis-infected host cells in the lung may provide a novel treatment strategy for pulmonary TB. In this study, a recombinant replication-deficient adenovirus serotype 5-based rAdhGLi was constructed that expressed human granulysin in the cytosol of the U937 and RAW264.7 macrophage-like cell lines as confirmed by western blotting and co-localization technology using indirect immunofluorescence staining. Ninety-six hours after both cell lines were infected with M. tuberculosis, acid-fast staining and enumeration demonstrated that rAdhGLi-treated cells had a lower colony-forming units (CFU) of intracellular bacteria than culture medium or AdNull controls. Granulysin was only expressed in the lung and not in other organs following inhalation of rAdhGLi. In particular, immunocompetent BALB/c mice or SCID mice intranasally infected with ~200 CFU of virulent M. tuberculosis H37Rv intranasally were treated with rAdhGLi, and they showed decreased bacterial loads in the lung when compared with phosphate-buffered saline or AdNull controls. Importantly, a clear dose-dependent rAdhGLi treatment efficacy was found in infected BALB/c mice, with the most significant reduction in lung bacteria obtained in BALB/c mice treated with 10(9) plaque-forming units of rAdhGLi without any pathological changes. Our study indicates that rAdhGLi may be used as a novel and efficient treatment strategy with the capability to directly kill intracellular M. tuberculosis.

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“…These ideas should be applied in future peptide‐based drug discovery. Furthermore, studies using peptides in combination with standard anti‐TB drugs have shown improved activity caused by increased cell permeation . The dosage of drugs and time required to destroy the pathogen was also reduced with combination treatments .…”

Section: Discussionmentioning

confidence: 99%

A review on anti‐tuberculosis peptides: Impact of peptide structure on anti‐tuberculosis activity

Yathursan

Wiles

Read

et al. 2019

Journal of Peptide Science

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Antibiotic resistance is a major public health problem globally. Particularly concerning amongst drug‐resistant human pathogens is Mycobacterium tuberculosis that causes the deadly infectious tuberculosis (TB) disease. Significant issues associated with current treatment options for drug‐resistant TB and the high rate of mortality from the disease makes the development of novel treatment options against this pathogen an urgent need. Antimicrobial peptides are part of innate immunity in all forms of life and could provide a potential solution against drug‐resistant TB. This review is a critical analysis of antimicrobial peptides that are reported to be active against the M tuberculosis complex exclusively. However, activity on non‐TB strains such as Mycobacterium avium and Mycobacterium intracellulare, whenever available, have been included at appropriate sections for these anti‐TB peptides. Natural and synthetic antimicrobial peptides of diverse sequences, along with their chemical structures, are presented, discussed, and correlated to their observed antimycobacterial activities. Critical analyses of the structure allied to the anti‐mycobacterial activity have allowed us to draw important conclusions and ideas for research and development on these promising molecules to realise their full potential. Even though the review is focussed on peptides, we have briefly summarised the structures and potency of the various small molecule drugs that are available and under development, for TB treatment.

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Enhanced susceptibility of multidrug resistant strains of Mycobacterium tuberculosis to granulysin peptides correlates with a reduced fitness phenotype

Cited by 26 publications

References 30 publications

Determinants of multidrug-resistant tuberculosis in Addis Ababa, Ethiopia

Determinants of multidrug-resistant tuberculosis in Addis Ababa, Ethiopia

Inhalation of recombinant adenovirus expressing granulysin protects mice infected with Mycobacterium tuberculosis

A review on anti‐tuberculosis peptides: Impact of peptide structure on anti‐tuberculosis activity

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