scholarly journals Cross-resistance of isoniazid, para-aminosalicylic acid and pasiniazid against isoniazid-resistant Mycobacterium tuberculosis isolates in China

2020 ◽  
Vol 20 ◽  
pp. 275-281
Author(s):  
Guilian Li ◽  
Jingrui Zhang ◽  
Yi Jiang ◽  
Li-li Zhao ◽  
Haican Liu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cross Resistance ◽  
Aminosalicylic Acid

scholarly journals Mutation ofRv2887, amarR-Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

2015 ◽  
Vol 59 (11) ◽  
pp. 6873-6881 ◽  
Author(s):  
Kathryn Winglee ◽  
Shichun Lun ◽  
Marco Pieroni ◽  
Alan Kozikowski ◽  
William Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Efflux Pump ◽  
Transcriptional Regulator ◽  
Cross Resistance ◽  
Loss Of Function ◽  
Strong Activity ◽  
Content Type ◽  
Novel Drug

ABSTRACTDrug resistance is a major problem inMycobacterium tuberculosiscontrol, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-a]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity againstM. tuberculosis. In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independentM. tuberculosismutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations inRv2887were common to all three MP-III-71-resistant mutants, and we confirmed the role ofRv2887as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified inEscherichia colito negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation ofRv2887abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations ofRv2887, encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance ofM. tuberculosisRv2887mutants may involve efflux pump upregulation and also drug methylation.

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 Lack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System

2020 ◽  
Vol 65 (1) ◽  
pp. e01914-20
Author(s):  
Anna E. Grzegorzewicz ◽  
Joël Lelièvre ◽  
Jorge Esquivias ◽  
Bhanupriya Angala ◽  
Jiuyu Liu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Phenotypic Screening ◽  
Whole Cell ◽  
Content Type ◽  
Fas Ii

ABSTRACTPhenotypic screening of inhibitors of the essential Mycobacterium tuberculosis FAS-II dehydratase HadAB led to the identification of GSK3011724A, a compound previously reported to inhibit the condensation step of FAS-II. Whole-cell-based and cell-free assays confirmed the lack of activity of GSK3011724A against the dehydratase despite evidence of cross-resistance between GSK3011724A and HadAB inhibitors. The nature of the resistance mechanisms is suggestive of alterations in the FAS-II interactome reducing access of GSK3011724A to KasA.

scholarly journals Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

2015 ◽  
Vol 59 (12) ◽  
pp. 7805-7810 ◽  
Author(s):  
Johana Rueda ◽  
Teresa Realpe ◽  
Gloria Isabel Mejia ◽  
Elsa Zapata ◽  
Juan Carlos Rozo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Content Type ◽  
Genotypic Analysis ◽  
Mdr Tb ◽  
Proportion Method ◽  
Emergence Of Resistance ◽  
Phenotypic Susceptibility

ABSTRACTEthionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in theMycobacterium tuberculosispopulation. ETH resistance inM. tuberculosisis phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in theinhApromoter and in the following genes:katG,ethA,ethR,mshA,ndh, andinhA. We sequenced the above genes in 64M. tuberculosisisolates (n= 57 ETH-resistant MDR-TB isolates;n= 3 ETH-susceptible MDR-TB isolates; andn= 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% inkatG, 72% inethA, 45.6% inmshA, 8.7% inndh, and 33.3% ininhAor its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations inkatG; one had a mutation inethA, and another, inmshAandinhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations inmshAgene unrelated to the resistance. Mutations not previously reported were found in theethA,mshA,katG, andndhgenes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in theM. tuberculosisisolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

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.

scholarly journals Disparities in Capreomycin Resistance Levels Associated with therrsA1401G Mutation in Clinical Isolates of Mycobacterium tuberculosis

2014 ◽  
Vol 59 (1) ◽  
pp. 444-449 ◽  
Author(s):  
Analise Z. Reeves ◽  
Patricia J. Campbell ◽  
Melisa J. Willby ◽  
James E. Posey
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Strong Predictor ◽  
Critical Concentration ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Second Line ◽  
Content Type

ABSTRACTAs the prevalence of multidrug-resistant and extensively drug-resistant tuberculosis strains continues to rise, so does the need to develop accurate and rapid molecular tests to complement time-consuming growth-based drug susceptibility testing. Performance of molecular methods relies on the association of specific mutations with phenotypic drug resistance and while considerable progress has been made for resistance detection of first-line antituberculosis drugs, rapid detection of resistance for second-line drugs lags behind. TherrsA1401G allele is considered a strong predictor of cross-resistance between the three second-line injectable drugs, capreomycin (CAP), kanamycin, and amikacin. However, discordance is often observed between therrsA1401G mutation and CAP resistance, with up to 40% ofrrsA1401G mutants being classified as CAP susceptible. We measured the MICs to CAP in 53 clinical isolates harboring therrsA1401G mutation and found that the CAP MICs ranged from 8 μg/ml to 40 μg/ml. These results were drastically different from engineered A1401G mutants generated in isogenicMycobacterium tuberculosis, which exclusively exhibited high-level CAP MICs of 40 μg/ml. These data support the results of prior studies, which suggest that the critical concentration of CAP (10 μg/ml) used to determine resistance by indirect agar proportion may be too high to detect all CAP-resistant strains and suggest that a larger percentage of resistant isolates could be identified by lowering the critical concentration. These data also suggest that differences in resistance levels among clinical isolates are possibly due to second site or compensatory mutations located elsewhere in the genome.

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