Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

Paolino, Marco; Brindisi, Margherita; Vallone, Alessandra; Butini, Stefania; Campiani, Giuseppe; Nannicini, Chiara; Giuliani, Germano; Anzini, Maurizio; Lamponi, Stefania; Giorgi, Gianluca; Sbardella, Diego; Ferraris, Davide M.; Marini, Stefano; Coletta, Massimo; Palucci, Ivana; Minerva, Mariachiara; Delogu, Giovanni; Pepponi, Ilaria; Goletti, Delia; Cappelli, Andrea; Gemma, Sandra; Brogi, Simone

doi:10.1002/cmdc.201700759

Cited by 37 publications

(32 citation statements)

References 33 publications

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“…Despite recent studies that have reported various virulence factors of MTB, relatively few studies have provided information on the difference in virulence among MTB drug-resistant strains. 20,[37][38][39] We compared the virulence of the six representative strains mainly based on the survival time in the mice, and results of which were also consistent with results from organ coefficient. Actually, we had chosen three mice in each group for histopathology, but there were no distinct differences between groups in pathology (results not shown).…”

Section: Discussionsupporting

confidence: 72%

Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug-Resistant Strains Induced from Mycobacterium tuberculosis in vitro

Wang

et al. 2020

IDR

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Purpose: Linezolid (LZD) and pretomanid (PA-824) are promising candidates in regimens for the treatment of drug-resistant tuberculosis. However, research on LZD and PA-824 dual drug-resistant (LPDR) strains is rarely reported. This study aimed to investigate the genotypic and virulence characteristics of LPDR strains. Methods: To obtain the LPDR strains (marked as LP or PL strains), we used a two-way induction method, namely, we first induced LZD-or PA-824-resistant mutants from the parental Mycobacterium tuberculosis (MTB) strain H37Rv in vitro, then we obtained the LPDR strains from induction of LZD-or PA-824-resistant mutants. Mutations in rplC, rrl, or ddn and fgd1 were identified in all mutants. To investigate the virulence of these strains, six strains were selected as representative strains, including LZD-resistant strains, PA-824resistant strains and LPDR strains. We performed the animal survival study as virulence of MTB can be measured as survival time of an animal after being infected. Results: We induced 38 mutant strains of LZD and PA-824 mono or dual drug resistance from H37Rv in vitro. The mutation frequency of rplC (C154R) gene in LPDR strains was 100% and 86%, respectively. In the animal survival study, animals infected with different drug-resistant strains survived significantly longer than those infected with H37Rv; animals infected with LPDR strains and PA-824-resistant strains survived similarly and both of which survived significantly shorter than those infected with LZD-resistant strains. Conclusion: Our study showed that rplC gene had a high mutation frequency in LPDR strains. The virulence of LPDR strains was similar to PA-824-resistant strains, and the virulence of the LZD-resistant strains was weaker than PA-824-resistant strains.

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Section: Discussionsupporting

confidence: 72%

Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug-Resistant Strains Induced from Mycobacterium tuberculosis in vitro

Wang

et al. 2020

IDR

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“…Zmp1 is a Zn-dependent metalloprotease which shares 31% homology and 48% similarity with both human peptidase neprilysin (NEP) and human endothelin-converting enzyme-1 (ECE-1), and the Zmp1 crystal structure revealed key residues that could be exploited for the design and development of specific inhibitors, especially regarding the nonconserved Arg615 and Arg616 [ 67 ]. Although the molecular partner(s) of Zmp1 has not been characterised, efforts have been made to identify Zmp1 substrate sequence specificity [ 68 ] and in the engineering and development of inhibitors against Zmp1 activity [ 69 , 70 ].…”

Section: M Tuberculosis Subversion Of the Hostmentioning

confidence: 99%

Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets

et al. 2018

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Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate the compliance and monitoring of drug administration and treatment. Moreover, the only available antitubercular vaccine fails to provide an effective shield against adult lung tuberculosis, which is the most prevalent form. Hence, there is a pressing need for effective antitubercular drugs and vaccines. This review highlights recent advances in the study of selected M. tuberculosis key molecular determinants of infection and vulnerable targets whose structures could be exploited for the development of new antitubercular agents.

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“…Protein preparation. SIRT1 three-dimensional structure in complex with RES was downloaded from Protein Data Bank (PDB) (PDB ID: 5BTR [23]) and submitted to the protein preparation wizard protocol implemented in Maestro suite 2018 (Protein Preparation Wizard workflow 2018) in order to obtain a reasonable starting structure for performing in silico studies [21,24].…”

Section: Computational Details Molecule Preparationmentioning

confidence: 99%

The Citrus Flavonoid Naringenin Protects the Myocardium from Ageing-Dependent Dysfunction: Potential Role of SIRT1

Testai

Piragine

Piano

et al. 2020

Oxidative Medicine and Cellular Longevity

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Sirtuin 1 (SIRT1) enzyme plays a pivotal role in the regulation of many physiological functions. In particular, it is implicated in ageing-related diseases, such as cardiac hypertrophy, myocardial infarct, and endothelial dysfunction; moreover, its expression decreases with age. Therefore, an effective strategy to extend the lifespan and improve cardiovascular function is the enhancement of the expression/activity of SIRT1 with exogenous agents. The Citrus flavonoid naringenin (NAR) presents structural similarity with the natural SIRT1 activator resveratrol. In this study, we demonstrate through in vitro assays that NAR significantly activates SIRT1 enzyme and shows antisenescence effects. The binding mode of NAR into SIRT1 was detailed investigated through in silico studies. Moreover, chronic administration (for six months) of NAR (100 mg/kg/day) to 6-month-old mice leads to an enhancement of SIRT1 expression and a marked reduction of reactive oxygen species production in myocardial tissue. Furthermore, at the end of the treatment, the plasma levels of two well-known markers of cardiovascular inflammation, TNF-α and IL6, are significantly reduced in 12-month-old mice treated with NAR, as well as the cardiovascular risk (total cholesterol/HDL ratio) compared to control mice. Finally, the age-associated fibrotic remodeling, which is well detected through a Mallory trichrome staining in the vehicle-treated 12-month-old mice, is significantly reduced by the chronic treatment with NAR. Moreover, an improvement of myocardium functionality is highlighted by the enhancement of citrate synthase activity and stabilization of the mitochondrial membrane potential after NAR treatment. Taken together, these results suggest that a nutraceutical approach with NAR may have positive impacts on many critical hallmarks of myocardial senescence, contributing to improve the cardiac performance in aged subjects.

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Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

Cited by 37 publications

References 33 publications

<p>Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug-Resistant Strains Induced from <em>Mycobacterium tuberculosis</em> in vitro</p>

<p>Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug-Resistant Strains Induced from <em>Mycobacterium tuberculosis</em> in vitro</p>

Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets

The Citrus Flavonoid Naringenin Protects the Myocardium from Ageing-Dependent Dysfunction: Potential Role of SIRT1

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