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Molecules (Basel, Switzerland) Oct 2022We evaluated the anti-mycobacterial effect of a flavonoid 5,7-dihydroxy-2-(4-hydroxyphenyl) 4-chromen-4-one () and two pyrimidines,...
We evaluated the anti-mycobacterial effect of a flavonoid 5,7-dihydroxy-2-(4-hydroxyphenyl) 4-chromen-4-one () and two pyrimidines, 4-hydroxy-2-dimethylamino-5-nitroso-6-aminopyrimidine () and 2-chloro-5--nonylpyrimidine () in vitro against (, H37Ra) and , using a Microplate Alamar Blue Assay (MABA). The effects of the compounds - in combination with first- and second-line anti-TB drugs isoniazid, rifampicin, cycloserine, and clarithromycin on the growth of and were also evaluated in in vitro assays. As a single agent, compounds and exhibited modest activity while compound was the most effective against and . When compounds - were evaluated at lower than 50% of their inhibitory concentrations in a two-drug combination with isoniazid or rifampicin, they showed additive to synergistic interactions. This inhibitory effect was improved when each of the three compounds was tested together in a three-drug combination with two of the first-line anti-TB drugs. Compounds - also demonstrated strong synergistic interaction in combination with cycloserine and clarithromycin in inhibiting the growth of and , respectively. This study demonstrated that compounds - have potential to be developed as effective anti-TB agents with combined use.
Topics: Antitubercular Agents; Clarithromycin; Cycloserine; Drug Combinations; Flavonoids; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Pyrimidines; Rifampin; Tuberculosis
PubMed: 36235249
DOI: 10.3390/molecules27196714 -
Frontiers in Cellular and Infection... 2022Tuberculosis (TB) is among the most difficult infections to treat, requiring several months of multidrug therapy to produce a durable cure. The reasons necessitating... (Review)
Review
Tuberculosis (TB) is among the most difficult infections to treat, requiring several months of multidrug therapy to produce a durable cure. The reasons necessitating long treatment times are complex and multifactorial. However, one major difficulty of treating TB is the resistance of the infecting bacterium, (Mtb), to many distinct classes of antimicrobials. This review will focus on the major gaps in our understanding of intrinsic drug resistance in Mtb and how functional and chemical-genetics can help close those gaps. A better understanding of intrinsic drug resistance will help lay the foundation for strategies to disarm and circumvent these mechanisms to develop more potent antitubercular therapies.
Topics: Humans; Mycobacterium tuberculosis; Drug Therapy, Combination; Leprostatic Agents; Antitubercular Agents; Tuberculosis, Lymph Node; Drug Resistance
PubMed: 36325467
DOI: 10.3389/fcimb.2022.997283 -
IUBMB Life Sep 2018More than a century has passed since the identification of Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis (TB), we still are nowhere close to... (Review)
Review
More than a century has passed since the identification of Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis (TB), we still are nowhere close to eradicating this deadly disease. Moreover, emergence of new drug-resistant strains has further complicated the situation, making it even more difficult to treat by conventional therapy regimens. Humans are the only reservoir for the existence and propagation of Mtb, which suggests that its latent forms will be most difficult to eradicate, till the human race lasts. Mtb has been associated with us for ages and its evolution is strictly guided to exploit its human host for survival and spread. The strategies employed by Mtb are unique and host specific, thereby making it hard to break this association without accurate understanding of this host-pathogen interaction. Metabolic pathways have always been at the heart of Mtb pathogenesis, with a continuous cross-talk between the pathogen and the host. Over the years, Mtb has mastered the art of manipulating the host machinery, along with modulating its own metabolism for survival in the hostile conditions. Here we aim to summarize the history of tuberculosis, its pathology and recent advances in basic understanding of the machinery, with eventual gape on the novel therapeutic strategies emerged in the past decade. © 2018 IUBMB Life, 70(9):917-925, 2018.
Topics: Animals; Antitubercular Agents; Drug Design; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 30129097
DOI: 10.1002/iub.1882 -
Molecules (Basel, Switzerland) Jan 2019has recently surpassed HIV/AIDS as the leading cause of death by a single infectious agent. The standard therapeutic regimen against tuberculosis (TB) remains a long,... (Review)
Review
has recently surpassed HIV/AIDS as the leading cause of death by a single infectious agent. The standard therapeutic regimen against tuberculosis (TB) remains a long, expensive process involving a multidrug regimen, and the prominence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) strains continues to impede treatment success. An underexplored class of natural products-the capuramycin-type nucleoside antibiotics-have been shown to have potent anti-TB activity by inhibiting bacterial translocase I, a ubiquitous and essential enzyme that functions in peptidoglycan biosynthesis. The present review discusses current literature concerning the biosynthesis and chemical synthesis of capuramycin and analogs, seeking to highlight the potential of the capuramycin scaffold as a favorable anti-TB therapeutic that warrants further development.
Topics: Aminoglycosides; Antitubercular Agents; Bacteria; Biocatalysis; Biological Products; Drug Discovery; Humans; Metabolic Networks and Pathways; Multigene Family; Mycobacterium tuberculosis; Structure-Activity Relationship
PubMed: 30691073
DOI: 10.3390/molecules24030433 -
Nature Communications Jun 2023Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that...
Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that have progressed through the drug discovery pipeline. These compounds are bicyclic nitroimidazoles that act as pro-drugs, requiring activation by a mycobacterial enzyme; however, the precise mechanisms of action of the active metabolite(s) are unclear. Here, we identify a molecular target of activated pretomanid and delamanid: the DprE2 subunit of decaprenylphosphoribose-2'-epimerase, an enzyme required for the synthesis of cell wall arabinogalactan. We also provide evidence for an NAD-adduct as the active metabolite of pretomanid. Our results highlight DprE2 as a potential antimycobacterial target and provide a foundation for future exploration into the active metabolites and clinical development of pretomanid and delamanid.
Topics: Antitubercular Agents; Molecular Targeted Therapy; Mycobacterium tuberculosis; Alcohol Oxidoreductases; Nitroimidazoles; Cell Wall; Drug Resistance; Prodrugs; Spectrophotometry; NAD; Kinetics
PubMed: 37380634
DOI: 10.1038/s41467-023-39300-z -
Expert Review of Clinical Pharmacology Mar 2018New and repurposed antituberculosis drugs are urgently needed to more safely and effectively treat multidrug-resistant (MDR) tuberculosis (TB) in children. Multiple... (Review)
Review
New and repurposed antituberculosis drugs are urgently needed to more safely and effectively treat multidrug-resistant (MDR) tuberculosis (TB) in children. Multiple challenges limit timely access to new MDR-TB treatments in children. Areas covered: Diagnosis of MDR-TB in children remains a barrier, with few children with MDR-TB diagnosed and treated. Other barriers to timely access to new and repurposed drugs are discussed, and include delayed initiation of paediatric trials, limited funding for paediatric drug development, fragmented regulatory systems and operational challenges. The status of access to current repurposed and novel drugs is presented. Expert commentary: More timely initiation of paediatric trials is needed and paediatric work should happen and be funded in parallel with each phase of adult trials. Better quality data, increased regulator resources and expertise, harmonization of regulatory requirements across borders/organisations and registration fee waivers would improve registration timelines. Improved diagnosis, recording and reporting will establish better demand. Improved systems for procurement and supply chain management would reduce in-country operational barriers to getting medications to children. The challenges must be addressed to ensure timely and equitable access to new drugs and regimens that are urgently needed for effective, safe and shorter treatment of children with MDR-TB.
Topics: Adult; Antitubercular Agents; Child; Drug Design; Drug Repositioning; Health Services Accessibility; Humans; Tuberculosis, Multidrug-Resistant
PubMed: 29280409
DOI: 10.1080/17512433.2018.1421067 -
Future Medicinal Chemistry Sep 2011Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi- and extensively drug-resistant strains of Mycobacterium... (Review)
Review
Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis poses a threat to management of global health. New drugs that effectively shorten the duration of treatment and are active against drug-resistant strains of this pathogen are urgently required to develop effective chemotherapies to combat this disease. Two nitroimidazoles, PA-824 and OPC-67683, are currently in Phase II clinical trials for the treatment of TB and the outcome of these may determine the future directions of drug development for anti-tubercular nitroimidazoles. In this review we summarize the development of these nitroimidazoles and alternative analogs in these series that may offer attractive alternatives to PA-824 and OPC-67683 for further development in the drug-discovery pipeline. Lastly, the potential pitfalls in the development of nitroimidazoles as drugs for TB are discussed.
Topics: Animals; Antitubercular Agents; Clinical Trials, Phase II as Topic; Drug Discovery; Drug Evaluation, Preclinical; Humans; Molecular Structure; Nitroimidazoles; Structure-Activity Relationship; Tuberculosis, Pulmonary
PubMed: 21879846
DOI: 10.4155/fmc.11.90 -
Accounts of Chemical Research Aug 2019Tuberculosis (TB) is the leading cause of mortality globally resulting from an infectious disease, killing almost 1.6 million people annually and accounting for... (Review)
Review
Tuberculosis (TB) is the leading cause of mortality globally resulting from an infectious disease, killing almost 1.6 million people annually and accounting for approximately 30% of deaths attributed to antimicrobial resistance (AMR). This despite the widespread administration of a neonatal vaccine, and the availability of an effective combination drug therapy against the causative agent, (Mtb). Instead, TB prevalence worldwide is characterized by high-burden regions in which co-epidemics, such as HIV, and social and economic factors, undermine efforts to control TB. These elements additionally ensure conditions that favor the emergence of drug-resistant Mtb strains, which further threaten prospects for future TB control. To address this challenge, significant resources have been invested in developing a TB drug pipeline, an initiative given impetus by the recent regulatory approval of two new anti-TB drugs. However, both drugs have been reserved for drug-resistant disease, and the seeming inevitability of new resistance plus the recognized need to shorten the duration of chemotherapy demands continual replenishment of the pipeline with high-quality "hits" with novel mechanisms of action. This represents a massive challenge, which has been undermined by key gaps in our understanding of Mtb physiology and metabolism, especially during host infection. Whereas drug discovery for other bacterial infections can rely on predictive in vitro assays and animal models, for Mtb, inherent metabolic flexibility and uncertainties about the nutrients available to infecting bacilli in different host (micro)environments instead requires educated predictions or demonstrations of efficacy in animal models of arguable relevance to human disease. Even microbiological methods for enumeration of viable mycobacterial cells are fraught with complication. Our research has focused on elucidating those aspects of mycobacterial metabolism that contribute to the robustness of the bacillus to host immunological defenses and applied antibiotics and that, possibly, drive the emergence of drug resistance. This work has identified a handful of metabolic pathways that appear vulnerable to antibiotic targeting. Those highlighted, here, include the inter-related functions of pantothenate and coenzyme A biosynthesis and recycling and nucleotide metabolism-the last of which reinforces our view that DNA metabolism constitutes an under-explored area for new TB drug development. Although nonessential functions have traditionally been deprioritized for antibiotic development, a common theme emerging from this work is that these very functions might represent attractive targets because of the potential to cripple mechanisms critical to bacillary survival under stress (for example, the Rel-dependent stringent response) or to adaptability under unfavorable, potentially lethal, conditions including antibiotic therapy (for example, DnaE2-dependent SOS mutagenesis). The bar, however, is high: demonstrating convincingly the likely efficacy of this strategy will require innovative models of human TB disease. In the concluding section, we focus on the need for improved techniques to elucidate mycobacterial metabolism during infection and its impact on disease outcomes. Here, we argue that developments in other fields suggest the potential to break through this barrier by harnessing chemical-biology approaches in tandem with the most advanced technologies. As researchers based in a high-burden country, we are impelled to continue participating in this important endeavor.
Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 31361123
DOI: 10.1021/acs.accounts.9b00275 -
Bioorganic & Medicinal Chemistry Letters Feb 2019The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a...
The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019-0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC = 40->120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.
Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Female; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Nitrofurans; Vero Cells
PubMed: 30600207
DOI: 10.1016/j.bmcl.2018.12.053 -
Frontiers in Cellular and Infection... 2022Tuberculosis, caused by (Mtb) is an ancient disease that has remained a leading cause of infectious death. Mtb has evolved drug resistance to every antibiotic regimen... (Review)
Review
Tuberculosis, caused by (Mtb) is an ancient disease that has remained a leading cause of infectious death. Mtb has evolved drug resistance to every antibiotic regimen ever introduced, greatly complicating treatment, lowering rates of cure and menacing TB control in parts of the world. As technology has advanced, our understanding of antimicrobial resistance has improved, and our models of the phenomenon have evolved. In this review, we focus on recent research progress that supports an updated model for the evolution of drug resistance in Mtb. We highlight the contribution of drug tolerance on the path to resistance, and the influence of heterogeneity on tolerance. Resistance is likely to remain an issue for as long as drugs are needed to treat TB. However, with technology driving new insights and careful management of newly developed resources, antimicrobial resistance need not continue to threaten global progress against TB, as it has done for decades.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Tuberculosis, Lymph Node; Drug Resistance; Biology
PubMed: 36275024
DOI: 10.3389/fcimb.2022.1027394