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Molecules (Basel, Switzerland) Mar 2020(MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent... (Review)
Review
(MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent anti-tubercular regimens can lead to the anticipated non-compliance of the patient and increased drug toxicity, which in turn can contribute to the emergence of drug-resistant MTB strains that are not susceptible to first- and second-line available drugs. Hence, there is an urgent need for innovative antitubercular drugs and vaccines. A number of biochemical processes are required to maintain the correct homeostasis of DNA metabolism in all organisms. Here we focused on reviewing our current knowledge and understanding of biochemical and structural aspects of relevance for drug discovery, for some such processes in MTB, and particularly DNA synthesis, synthesis of its nucleotide precursors, and processes that guarantee DNA integrity and genome stability. Overall, the area of drug discovery in DNA metabolism appears very much alive, rich of investigations and promising with respect to new antitubercular drug candidates. However, the complexity of molecular events that occur in DNA metabolic processes requires an accurate characterization of mechanistic details in order to avoid major flaws, and therefore the failure, of drug discovery approaches targeting genome integrity.
Topics: Antitubercular Agents; DNA Repair; DNA Replication; Drug Discovery; Genome, Bacterial; Mycobacterium tuberculosis; Ribonucleotides
PubMed: 32156001
DOI: 10.3390/molecules25051205 -
Biomedical Chromatography : BMC Dec 2017Lansoprazole (LPZ) is a commercially available proton-pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in...
Lansoprazole (LPZ) is a commercially available proton-pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis. It was also reported that a 300 mg kg oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL , respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti-TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti-TB compound.
Topics: Administration, Oral; Animals; Antitubercular Agents; Chromatography, Liquid; Female; Lansoprazole; Linear Models; Lung; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry
PubMed: 28623874
DOI: 10.1002/bmc.4035 -
Current Topics in Medicinal Chemistry 2021Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent, mainly due to Mycobacterium tuberculosis... (Review)
Review
Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent, mainly due to Mycobacterium tuberculosis (MTB). Recently, clinical prognoses have worsened due to the emergence of multi-drug resistant (MDR) and extensive-drug resistant (XDR) tuberculosis, which lead to the need for new, efficient and safe drugs. Among the several strategies, polypharmacology could be considered one of the best solutions, in particular, the multitarget directed ligands strategy (MTDLs), based on the synthesis of hybrid ligands acting against two targets of the pathogen. The framework strategy comprises linking, fusing and merging approaches to develop new chemical entities. With these premises, this review aims to provide an overview of the recent hybridization approach, in medicinal chemistry, of the most recent and promising multitargeting antimycobacterial candidates.
Topics: Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Nucleic Acid Hybridization
PubMed: 32814528
DOI: 10.2174/1568026620666200819151342 -
CNS Drugs Aug 2010Nervous system toxicity with current antituberculosis pharmacotherapy is relatively uncommon, although the frequency of the usage of antituberculosis therapy requires... (Review)
Review
Nervous system toxicity with current antituberculosis pharmacotherapy is relatively uncommon, although the frequency of the usage of antituberculosis therapy requires that physicians be aware of such toxicity. Antituberculosis therapy manifests both central and peripheral nervous system effects, which may compromise patient compliance. Among the traditional forms of first-line antituberculosis therapy, isoniazid is most often associated with nervous system effects, most prominently peripheral neuropathy, psychosis and seizures. Adverse events are reported with other antituberculosis therapies, the most prominent being optic neuropathy with ethambutol and ototoxicity and neuromuscular blockade with aminoglycosides. The second-line agent with the most adverse effects is cycloserine, with psychosis and seizures, the psychosis in particular limiting its usage. Fluoroquinolones are rare causes of seizures and delirium. Newer forms of therapy are under development, but to date no significant neurotoxicity is documented with these agents. Future needs include the development of surveillance mechanisms to increase recognition of nervous system toxicities. It is also hoped that the development of new pharmacogenomic assays will help with the identification of patients at risk for these toxicities.
Topics: Animals; Antitubercular Agents; Central Nervous System; Female; Humans; Male; Mycobacterium tuberculosis; Nervous System Diseases; Peripheral Nervous System; Tuberculosis
PubMed: 20658798
DOI: 10.2165/11534340-000000000-00000 -
Drug Development Research Aug 2019There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8-hydroxyquinoline series is a...
There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8-hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure-activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8-hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 μM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub-family of 2-styryl-substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC of <100 μM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8-hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.
Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Hep G2 Cells; Humans; Hydroxyquinolines; Microbial Sensitivity Tests; Microbial Viability; Molecular Structure; Mycobacterium tuberculosis; Oxyquinoline; Structure-Activity Relationship; Vero Cells
PubMed: 30893501
DOI: 10.1002/ddr.21531 -
Chemical & Pharmaceutical Bulletin Apr 2019A series of meta-amido bromophenol derivatives were designed and synthesized. The compounds were found to potently inhibit the growth of Mycobacterium tuberculosis...
A series of meta-amido bromophenol derivatives were designed and synthesized. The compounds were found to potently inhibit the growth of Mycobacterium tuberculosis H37Ra. They also exhibited moderate inhibitory activity against Mycobacterium tuberculosis H37Rv and multidrug-resistant strains. The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. Moderate cytotoxicities and good metabolic stability were observed for the selected compounds. The results demonstrated meta-amido bromophenols as a new class of antitubercular agents with good potentials.
Topics: Antitubercular Agents; Drug Design; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenols; Structure-Activity Relationship
PubMed: 30686792
DOI: 10.1248/cpb.c18-00917 -
European Journal of Medicinal Chemistry Jan 2017Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and...
Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 μM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.
Topics: Antifungal Agents; Antitubercular Agents; Drug Design; Drug Resistance; Hep G2 Cells; Humans; Microbial Sensitivity Tests; Oxadiazoles; Structure-Activity Relationship; Sulfhydryl Compounds; Tetrazoles
PubMed: 27907875
DOI: 10.1016/j.ejmech.2016.11.041 -
The Medical Clinics of North America Nov 1993The management of MDR-TB requires that the clinician become familiar with the "second-line" antimycobacterial agents. These drugs are generally less potent and... (Review)
Review
The management of MDR-TB requires that the clinician become familiar with the "second-line" antimycobacterial agents. These drugs are generally less potent and frequently more toxic than isoniazid and rifampin. Because they are less active, innovative dosing schedules may allow us to take advantage of the few strengths that they possess. This approach will require further research into the dose-response relationships for each agent. Based on our current knowledge of these drugs, practical guidelines for their use have been described. These guidelines include the gradual escalation of the oral doses of PAS, cycloserine, and ethionamide over several days, and the intravenous administration of streptomycin and capreomycin. Both ciprofloxacin and ofloxacin may be used for the treatment of MDR-TB, but data from clinical trials are currently lacking. Finally, because patients with AIDS appear to develop antimycobacterial drug malabsorption over the course of their HIV infection, therapeutic drug monitoring can be used to verify drug absorption in the individual patient. This approach may improve therapy for that patient and prevent the selection of additional drug resistance.
Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 8231410
DOI: 10.1016/s0025-7125(16)30191-2 -
Antimicrobial Agents and Chemotherapy Jul 2018Tuberculosis is a major global health problem, and the emergence of multidrug-resistant and extensively drug-resistant strains has increased the difficulty of treating...
Tuberculosis is a major global health problem, and the emergence of multidrug-resistant and extensively drug-resistant strains has increased the difficulty of treating this disease. Among the novel antituberculosis drugs in the pipeline, decaprenylphosphoryl-beta-d-ribose-2-epimerase (DprE1) inhibitors such as BTZ043 and pBTZ169 exhibited extraordinary antituberculosis potency. Here, the metabolites of the new DprE1 inhibitor SKLB-TB1001 and its inhibition of cytochrome P450 isoforms and plasma protein binding (PPB) were studied. The results showed that rapid transformation and high PPB resulted in inadequate exposure and thus led to the moderate potency of SKLB-TB1001 This study provided explanations for the discrepant potency of this scaffold and Meanwhile, it also provides a rationale for lead optimization of this very promising scaffold of antituberculosis agents to prevent them from being metabolized, thus improving their exposure .
Topics: Animals; Antitubercular Agents; Bacterial Proteins; Mice; Molecular Structure; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tandem Mass Spectrometry; Tuberculosis
PubMed: 29686156
DOI: 10.1128/AAC.02375-17 -
Hong Kong Medical Journal = Xianggang... Feb 2006To review the literature on ocular toxicity of ethambutol--its background, clinical presentation, toxicity characteristics, management, monitoring, and preventive... (Review)
Review
OBJECTIVE
To review the literature on ocular toxicity of ethambutol--its background, clinical presentation, toxicity characteristics, management, monitoring, and preventive measures.
DATA SOURCES
Literature search of Medline from 1962 to May 2005.
STUDY SELECTION
All related literature in English using the search formula: (ethambutol OR myambutol) AND (eye* OR ophthal* OR ocular) AND (adverse OR toxic).
DATA EXTRACTION
All information was collected and analysed by authors.
DATA SYNTHESIS
Ethambutol hydrochloride is a commonly used first-line anti-tuberculous agent. Although rare, ocular toxicity in the form of optic neuritis (most commonly retrobulbar neuritis) has been well documented since its first use in the 1960s. Classically described as dose- and duration-related and reversible on therapy discontinuation, reversibility of optic neuritis remains controversial. International guidelines on prevention and early detection of ethambutol-induced ocular toxicity have been published. Nonetheless, opinion of the clinical effectiveness of regular vision tests to enable early detection of toxicity is divided.
CONCLUSIONS
The course of ethambutol-induced ocular toxicity is unpredictable. Measures to ensure a high level of awareness in medical staff and patients of this potential adverse effect appear to be the best current preventive method. Classified by the World Health Organization as a place with an intermediate tuberculosis burden and good health infrastructure, Hong Kong is in a good position to examine the unanswered questions about ethambutol-induced ocular toxicity.
Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Ethambutol; Humans; Optic Neuritis; Practice Guidelines as Topic; Recovery of Function; Time Factors
PubMed: 16495590
DOI: No ID Found