Atom based 3D QSAR and Fingerprint based 2D QSAR of Novel Molecules as MmpL3 receptor inhibitors for Mycobacterium tuberculosis

2021 ◽  
pp. 6321-6329
Author(s):  
Poojita K ◽  
Fajeelath Fathima ◽  
Rajdeep Ray ◽  
Lalit Kumar ◽  
Ruchi Verma
Keyword(s):  
Health Care ◽  
Mycobacterium Tuberculosis ◽  
3D Qsar ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Urea Derivatives ◽  
2D Qsar ◽  
Qsar Models ◽  
Inhibition Property ◽  
Anti Tubercular Therapy

Tuberculosis is one of the leading cause of increase in mortality rate in today’s health care scenario. Due to increase frequency of drug resistant TB it is prudent to find new targets and promising targets for anti-tubercular activity. MmpL3 (Mycobacterial Membrane Protein Large 3) is one of the most effective and promiscuous targets for development of new drug for anti-tubercular therapy due to its cross resistance inhibition property. In this study we have presented atom based 3D QSAR and finger print based 2D QSAR models to study different structural and functional groups of Adamantyl urea derivatives and their action in MmpL3 inhibitory activity which will provide us the insight for designing better and far more effective anti TB drugs.

scholarly journals Aminoglycoside Cross-Resistance in Mycobacterium tuberculosis Due to Mutations in the 5′ Untranslated Region ofwhiB7

2013 ◽  
Vol 57 (4) ◽  
pp. 1857-1865 ◽  
Author(s):  
Analise Z. Reeves ◽  
Patricia J. Campbell ◽  
Razvan Sultana ◽  
Seidu Malik ◽  
Megan Murray ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Untranslated Region ◽  
Regulatory Region ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Second Line ◽  
Content Type ◽  
Low Level ◽  
Level Resistance

ABSTRACTSince the discovery of streptomycin's bactericidal activity againstMycobacterium tuberculosis, aminoglycosides have been utilized to treat tuberculosis (TB). Today, the aminoglycosides kanamycin and amikacin are used to treat multidrug-resistant (MDR) TB, and resistance to any of the second-line injectable antibiotics, including kanamycin, amikacin, or capreomycin, is a defining characteristic of extensively drug-resistant (XDR) TB. Resistance to kanamycin and streptomycin is thought to be due to the acquisition of unlinked chromosomal mutations. However, we identified eight independent mutations in the 5′ untranslated region of the transcriptional activatorwhiB7that confer low-level resistance to both aminoglycosides. The mutations lead to 23- to 145-fold increases inwhiB7transcripts and subsequent increased expression of botheis(Rv2416c) andtap(Rv1258c). Increased expression ofeisconfers kanamycin resistance in these mutants, while increased expression oftap, which encodes an efflux pump, is a previously uncharacterized mechanism of low-level streptomycin resistance. Additionally, high-level resistance to streptomycin arose at a much higher frequency inwhiB7mutants than in a wild-type (WT) strain. AlthoughwhiB7is typically associated with intrinsic antibiotic resistance inM. tuberculosis, these data suggest that mutations in an uncharacterized regulatory region ofwhiB7contribute to cross-resistance against clinically used second-line antibiotics. As drug resistance continues to develop and spread, understanding the mechanisms and molecular basis of antibiotic resistance is critical for the development of rapid molecular tests to diagnose drug-resistant TB strains and ultimately for designing regimens to treat drug-resistant cases of TB.

Predicting the potency of hERG K+ channel inhibition by combining 3D-QSAR pharmacophore and 2D-QSAR models

2011 ◽  
Vol 18 (3) ◽  
pp. 1023-1036 ◽  
Author(s):  
Yayu Tan ◽  
Yadong Chen ◽  
Qidong You ◽  
Haopeng Sun ◽  
Manhua Li
Keyword(s):  
3D Qsar ◽  
K Channel ◽  
2D Qsar ◽  
Channel Inhibition ◽  
Qsar Models

Synthesis and activity of BNF15 against drug-resistant Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Hafij Al Mahmud ◽  
Hoonhee Seo ◽  
Sukyung Kim ◽  
Md Imtiazul Islam ◽  
Omme Fatema Sultana ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Toxic Effect ◽  
Toxicity Test ◽  
Nontuberculous Mycobacteria ◽  
Drug Resistant ◽  
Acute Oral Toxicity ◽  
Oral Toxicity ◽  
Antibiotic Effect ◽  
Anti Tubercular Therapy ◽  
Post Antibiotic Effect

Aim: Tuberculosis is the leading cause of mortality among infectious diseases worldwide. Finding a new competent anti tubercular therapy is essential. Materials & methods: We screened thousands of compounds and evaluated their efficacy against Mycobacterium tuberculosis. Results: Initially, 2-nitronaphtho[2,3-b]benzofuran-6,11-dione was active against M. tuberculosis. Next, among x15 newly synthesized derivatives, BNF15 showed promising effect against all drug-sensitive and drug-resistant M. tuberculosis (MIC: 0.02–0.78 μg/ml). BNF15 effectively killed intracellular M. tuberculosis and nontuberculous mycobacteria. BNF15 exhibited a prolonged post antibiotic effect superior to isoniazid, streptomycin, and ethambutol and synergistic interaction with rifampicin. In acute oral toxicity test, BNF15 did not show toxic effect at a concentration up to 2000 mg/kg. Conclusion: These results highlight the perspective of BNF15 to treat drug-resistant M. tuberculosis.

scholarly journals 1H-Benzo[d]Imidazole Derivatives Affect MmpL3 in Mycobacterium tuberculosis

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Małgorzata Korycka-Machała ◽  
Albertus Viljoen ◽  
Jakub Pawełczyk ◽  
Paulina Borówka ◽  
Bożena Dziadek ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycolic Acid ◽  
Cross Resistance ◽  
Metabolic Labeling ◽  
Drug Resistant ◽  
Content Type ◽  
Antitubercular Drugs ◽  
Imidazole Derivatives ◽  
Trehalose Dimycolate

ABSTRACT 1H-benzo[d]imidazole derivatives exhibit antitubercular activity in vitro at a nanomolar range of concentrations and are not toxic to human cells, but their mode of action remains unknown. Here, we showed that these compounds are active against intracellular Mycobacterium tuberculosis. To identify their target, we selected drug-resistant M. tuberculosis mutants and then used whole-genome sequencing to unravel mutations in the essential mmpL3 gene, which encodes the integral membrane protein that catalyzes the export of trehalose monomycolate, a precursor of the mycobacterial outer membrane component trehalose dimycolate (TDM), as well as mycolic acids bound to arabinogalactan. The drug-resistant phenotype was also observed in the parental strain overexpressing the mmpL3 alleles carrying the mutations identified in the resistors. However, no cross-resistance was observed between 1H-benzo[d]imidazole derivatives and SQ109, another MmpL3 inhibitor, or other first-line antitubercular drugs. Metabolic labeling and quantitative thin-layer chromatography (TLC) analysis of radiolabeled lipids from M. tuberculosis cultures treated with the benzoimidazoles indicated an inhibition of trehalose dimycolate (TDM) synthesis, as well as reduced levels of mycolylated arabinogalactan, in agreement with the inhibition of MmpL3 activity. Overall, this study emphasizes the pronounced activity of 1H-benzo[d]imidazole derivatives in interfering with mycolic acid metabolism and their potential for therapeutic application in the fight against tuberculosis.

scholarly journals Experimental confirmation that an uncommon, yet clinically relevant mutation (G878A) in the rrs gene of Mycobacterium tuberculosis confers resistance to streptomycin.

2021 ◽  
Author(s):  
Pilar Domenech ◽  
Esma Mouhoub ◽  
Michael B Reed
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Aminoglycoside Antibiotic ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Gene Encoding ◽  
Experimental Proof ◽  
Phenotypic Resistance ◽  
Resistant Tuberculosis ◽  
Predictive Functions

The effective treatment of patients diagnosed with drug resistant tuberculosis (TB) is highly dependent upon the ability to rapidly and accurately determine the antibiotic resistance/ susceptibility profile of the Mycobacterium tuberculosis isolate(s) involved. Thus, as more and more clinical microbiology laboratories advance towards the routine use of DNA sequence-based diagnostics, it is imperative that their predictive functions extend beyond the well-known resistance-conferring mutations, in order to also encompass as many of the lower-frequency mutations as possible. However, in most cases, the fundamental experimental proof that links these uncommon mutations with phenotypic resistance is still lacking. One such example is the G878A polymorphism within the rrs gene encoding the 16s rRNA. We, and others, have identified this mutation within a small number of drug-resistant M. tuberculosis isolates, although prior to this study a consensus regarding exactly which aminoglycoside antibiotic(s) it conferred resistance toward seems not to have been reached. Here we have employed oligo-mediated recombineering to specifically introduce the G878A polymorphism into the rrs gene of M. bovis BCG - a species very closely related to M. tuberculosis - and demonstrate that it confers low-level resistance to streptomycin alone. In our hands, it does not confer cross-resistance towards amikacin, capreomycin, nor kanamycin. We also demonstrate that the rrsG878A mutation exerts a substantial fitness defect in vitro, that may at least in part explain why clinical M. tuberculosis isolates bearing this mutation appear to be quite rare. Overall, this study provides clarity to the resistance phenotype attributable to the rrsG878A mutation and is relevant to the future implementation of genomics-based diagnostics, as well as the clinical management of patients in situations where this particular polymorphism is encountered.

Identifying the Structural Features of Diphenyl Ether Analogues for InhA Inhibition: A 2D and 3D QSAR Based Study

2019 ◽  
Vol 17 (1) ◽  
pp. 31-47 ◽  
Author(s):  
Ashutosh Prasad Tiwari ◽  
Varadaraj Bhat Giliyar ◽  
Gurypur Gautham Shenoy ◽  
Vandana Kalwaja Eshwara
Keyword(s):  
Inhibitory Activity ◽  
Diphenyl Ether ◽  
3D Qsar ◽  
Qsar Model ◽  
Structural Features ◽  
Mycolic Acids ◽  
2D Qsar ◽  
Qsar Models ◽  
Mycobacterial Cell Wall ◽  
2D And 3D

Background: Enoyl acyl carrier protein reductase (InhA) is a validated target for Mycobacterium. It is an enzyme which is associated with the biosynthesis of mycolic acids in type II fatty acid synthase system. Mycobacterial cell wall majorly comprises mycolic acids, which are responsible for virulence of the microorganism. Several diphenyl ether derivatives have been known to be direct inhibitors of InhA. Objective: In the present work, a Quantitative Structure Activity Relationship (QSAR) study was performed to identify the structural features of diphenyl ether analogues which contribute to InhA inhibitory activity in a favourable way. Method: Both 2D and 3D QSAR models were built and compared. Several fingerprint based 2D QSAR models were generated and their relationship with the structural features was studied. Models which corroborated the inhibitory activity of the molecules with their structural features were selected and studied in detail. Results: A 2D-QSAR model, with dendritic fingerprints having regression coefficient, for test set molecules Q2 =0.8132 and for the training set molecules, R2 =0.9607 was obtained. Additionally, an atom-based 3D-QSAR model with Q2 =0.7697 and R2 =0.9159 was also constructed. Conclusion: The data reported by various models provides guidance for the designing of structurally new diphenyl ether inhibitors with potential activity against InhA of M. tuberculosis.

scholarly journals Discordant Resistance to Kanamycin and Amikacin in Drug-Resistant Mycobacterium tuberculosis

2003 ◽  
Vol 47 (9) ◽  
pp. 2971-2973 ◽  
Author(s):  
Annika Krüüner ◽  
Pontus Jureen ◽  
Klavdia Levina ◽  
Solomon Ghebremichael ◽  
Sven Hoffner
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Kanamycin Resistance ◽  
Cross Resistance ◽  
Drug Resistant

ABSTRACT It is generally thought that there is full cross-resistance in Mycobacterium tuberculosis between the aminoglycoside drugs kanamycin and amikacin. However, kanamycin resistance and amikacin susceptibility were seen in 43 of 79 (54%) multidrug-resistant Estonian isolates, indicating that there might be a need to test the resistance of M. tuberculosis isolates to both drugs.

scholarly journals Toward a Phage Cocktail for Tuberculosis: Susceptibility and Tuberculocidal Action of Mycobacteriophages against Diverse Mycobacterium tuberculosis Strains

mBio ◽  
2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Carlos A. Guerrero-Bustamante ◽  
Rebekah M. Dedrick ◽  
Rebecca A. Garlena ◽  
Daniel A. Russell ◽  
Graham F. Hatfull
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Genome Engineering ◽  
Therapeutic Potential ◽  
Mycobacterium Abscessus ◽  
Cross Resistance ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Content Type ◽  
Phage Cocktail ◽  
Mdr Tb

ABSTRACT The global health burden of human tuberculosis (TB) and the widespread antibiotic resistance of its causative agent Mycobacterium tuberculosis warrant new strategies for TB control. The successful use of a bacteriophage cocktail to treat a Mycobacterium abscessus infection suggests that phages could play a role in tuberculosis therapy. To assemble a phage cocktail with optimal therapeutic potential for tuberculosis, we have explored mycobacteriophage diversity to identify phages that demonstrate tuberculocidal activity and determined the phage infection profiles for a diverse set of strains spanning the major lineages of human-adapted strains of the Mycobacterium tuberculosis complex. Using a combination of genome engineering and bacteriophage genetics, we have assembled a five-phage cocktail that minimizes the emergence of phage resistance and cross-resistance to multiple phages, and which efficiently kills the M. tuberculosis strains tested. Furthermore, these phages function without antagonizing antibiotic effectiveness, and infect both isoniazid-resistant and -sensitive strains. IMPORTANCE Tuberculosis kills 1.5 million people each year, and resistance to commonly used antibiotics contributes to treatment failures. The therapeutic potential of bacteriophages against Mycobacterium tuberculosis offers prospects for shortening antibiotic regimens, provides new tools for treating multiple drug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB infections, and protects newly developed antibiotics against rapidly emerging resistance to them. Identifying a suitable suite of phages active against diverse M. tuberculosis isolates circumvents many of the barriers to initiating clinical evaluation of phages as part of the arsenal of antituberculosis therapeutics.

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