A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator
Marte S. DragsetGiovanna PoceSalvatore AlfonsoTeresita Padilla‐BenavidesThomas R. IoergerTakushi KanekoJames C. SacchettiniMariangela BiavaTanya ParishJosé ArgüelloMagnus SteigedalEric J. Rubin
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ABSTRACT Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis . Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.Keywords:
Antimycobacterial
Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains one of the deadliest, infectious diseases worldwide. The detrimental effects caused by the existing anti-TB drugs to TB patients and the emergence of resistance strains of M. tuberculosis has driven efforts from natural products researchers around the globe in discovering novel anti-TB drugs that are more efficacious and with less side effects. There were eleven main review publications that focused on natural products with anti-TB potentials. However, none of them specifically emphasized antimycobacterial phenolic compounds. Thus, the current review’s main objective is to highlight and summarize phenolic compounds found active against mycobacteria from 2000 to 2017. Based on the past studies in the electronic databases, the present review also focuses on several test organisms used in TB researches and their different distinct properties, a few types of in vitro TB bioassay and comparison between their strengths and drawbacks, different methods of extraction, fractionation and isolation, ways of characterizing and identifying isolated compounds and the mechanism of actions of anti-TB phenolic compounds as reported in the literature.
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Background: In our on-going efforts towards tuberculosis (TB) drug discovery programme, a high-throughput whole cell-based phenotypic screening of thousands of compounds against Mycobacterium tuberculosis H37Rv lead to the identification of a lead compound; 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD). In our earlier studies, it was observed that the test compound exhibited antimicrobial activity that was restricted to M. tuberculosis only. The test compound also proved to be non-toxic against a panel of human cell lines. Therefore, the present study was planned with an aim to further explore the antimycobacterial potential of the PAMCHD against M. tuberculosis H37Rv. Methods & Materials: In this study, we determined the minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) of the PAMCHD. Kill curve and drug interaction studies were performed. Effect of serum/protein binding on PAMCHD activity was explored. Further, post antibiotic effect (PAE), Mutation frequency (MF) and mutant prevention concentration (MPC) were studied. Results: PAMCHD proved to be tuberculostatic (MIC, 2.5 μg/mL) as well as tuberculocidal (MBC, 5.0 μg/mL) agent. This compound was equipotent against drug resistant M. tuberculosis clinical isolates (MIC, 2.5-10 μg/mL). The dynamics of M. tuberculosis killing revealed its time as well as concentration-dependent anti-TB activity with an Emax of 10.0 μg/mL (at this concentration M.tuberculosis culture were completely sterilized). PAMCHD acts synergistically and additively with key first line and second line ATDs respectively. PAE of PAMCHD's was found to be 63.1 and 103.8 h at 4x and 8x MIC and that of INH (used as a control ATD) were 39.8 and 127.9 h respectively. MF for M. tuberculosis against PAMCHD was lower than that of INH at all the tested concentrations. The capacity of preventing emergence of resistant mutants of PAMCHD was found to be comparable to rifampin (RIF) as mutant MPC of both was observed to be 160 μg/mL. MPC/MIC value of PAMCHD (i.e. 64) matched to the best-known value among ATDs (i.e. 68) exhibited by moxifloxacin reflecting its additional significant potential to prevent emergence of resistant mutants. Conclusion: PAMCHD bears significant antituberculosis potential proven at various levels that warrant its further evaluation towards TB drug development.
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Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (M. tuberculosis), killing about two million people worldwide each year. An increase in the prevalence of drug-resistant strains of M. tuberculosis in the past decades has renewed focus on the development of new drugs that can treat both drug-sensitive and resistant TB infections. M. tuberculosis evades the host immune system and drug regimes by entering dormant phase within macrophage. As a consequence, there is a pressing need for new vaccines and antimicrobials to treat persistent infections. As clinically used antibiotics target very few essential functions of mycobacterium, it is rational that identification of new targets that are essential for bacterial growth and survival can serve as starting point for designing of novel drugs to cure both drug-sensitive and resistant TB infections. With the development of molecular biology and structural biology and the availability of the genome sequence of M. tuberculosis, some success has been achieved in the identification of new targets in M. tuberculosis and their relevant inhibitors. This review summarizes about ninety important targets that participate in a range of diverse physiological processes in M. tuberculosis and seven new drugs currently in clinical phase 2 or 3 trials. In addition, promising inhibitors with novel mechanisms of action and clinical vaccine candidates are highlighted. Keywords: Antimycobacterial, dormant, drug-resistant, inhibitors, Mycobacterium tuberculosis, new targets.
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The aim: To analyze the changes in indicators of tuberculosis mycobacteria sensitivity to anti-mycobacterial drugs over the past nine years in Ternopol region (Ukraine) and to develop recommendations for the use of drug combinations in this region. Materials and methods: The medical examinations were carried out in the Clinical and Diagnostic Laboratory of Ternopil Regional Tuberculosis Hospital during 2007-2017. Sensitivity analysis was carried out on a solid Löwenstein-Jensen medium and in liquid Meedlebrook medium using automatic bacteriological BACTEC 1443 tests with addition to the media of first line anti-TB drugs. Results: The sensitivity of Mycobacterium tuberculosis to anti-TB drugs has decreased in 2017 comparing to 2007, both among new cases and relapses of the disease.During this period in newly diagnosed patients the number of M. tuberculosis sensitive to first-line anti-TB drugs has decreased by 6.1%. Conclusions: Considering the increase in multi-resistant pathogens in newly diagnosed and relapsed of tuberculosis cases, it is necessary to use a modern express methods of diagnostics for the causative agents of tuberculosis and to study their sensitivity to antimycobacterial drugs, especially by using molecular genetics methods.
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This chapter introduces Mycobacterium tuberculosis , the agent that causes tuberculosis and the drugs (first- and second-line) for tuberculosis treatment as well as the effects of phytochemicals against Mycobacterium tuberculosis . It starts by giving an overview of the organism and the disease burden of tuberculosis. It then explains the potential plants with antimycobacterial properties, phytochemicals/plant metabolites against Mycobacterium tuberculosis as well as phytochemicals against multidrug resistant tuberculosis. At the end of this chapter, the therapeutic potential of phytochemicals against Mycobacterium tuberculosis was discussed. A discussion on phenolic compounds as potential drugs for tuberculosis and prospects of phytochemicals against Mycobacterium tuberculosis was included.
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Tuberculosis (TB) is a devastating disease responsible for millions of humans’ deaths worldwide. It is caused by a mycobacterial organism, the tubercle bacillus or Mycobacterium tuberculosis. Although TB can be treated, cured and can be prevented if patients take prescribed medicines, scientists have never come close to wiping it out due to a sharp rise in the incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) mycobacterium strains. Due to long regimen treatment and emergence of MDR and XDR-TB, it is urgent to re-engineer and reposition old drugs for developing new antimycobacterial entities with novel mechanisms of action to achieve effective TB control even against the resistant forms of TB. To combat the dreadful MDR and XDR-TB, potential targets are being extensively searched for the last couple of years for the design and discovery of active potential antitubercular chemotherapeutics. To explore the disease virulence, potential new tubercular target enzymes such as InhA, MmpL3, ATP synthase, DprE1, QcrB and MenA have been taken into consideration in the present study and the structure-based design of the corresponding target inhibitors which are under clinical investigation has been attempted to identify structural features for the discovery of new chemical entities (NCEs) having specificity towards MDR and XDR Mycobacterium tuberculosis (M. tuberculosis).
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Summary: In search of new anti-mycobacterial agents seven acyl and one benzyl derivatives of coniferyl alcohol were synthesized and evaluated along with coniferyl alcohol for antitubercular activity against Mycobacterium tuberculosis H37Rv (Mtb) in vitro . Four compounds ( 3 - 6 ) showed greater activity than the parent compound and inhibited MTB with IC 90 9.11, 8.92, 4.28 and 3.01 µ g/mL respectively. Compound 6, the most potent compound in vitro exhibited CC 50 10.216 µ g/mL in VERO cells with selectivity index 3.394. Reference compounds used were rifampin and isoniazid and had IC 90 0.0031 and 0.063 µ g/mL respectively. Keywords: Coniferyl alcohol; acyl and benzyl derivatives; antitubercular activity; Mycobacterium tuberculosis H37Rv. Introduction Tuberculosis caused by mycobacteria, primarily Mycobacterium tuberculosis , is one of the most fatal infectious chronic diseases infecting about one third of the world’s population and causing eight million new infections annually and three million deaths per year [1]. New infections as well as re-activation of latent tuberculosis are particularly associated with compromised immune systems, such as individuals who are HIV positive. AIDS patients have a higher risk of developing tuberculosis than the normal individuals. Further, tuberculosis has more chances of spreading by airborne transmission also to persons without any history of AIDS [2]. Furthermore, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) cases are also on a rise which are more difficult to be treated [3]. In Pakistan over 200 people in 100,000 are the victims of this fatal disease [4]. This scenario requires an urgent search of new and more effective anti-tuberculosis agents which can combat the problems associated with present treatment of tuberculosis. A few years before we reported the isolation and structure elucidation of a natural product, lawsonicin from a medicinal plant
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