Mechanisms of Drug Action, Drug Resistance and Drug Tolerance in<i>Mycobacterium tuberculosis</i>: Expected Phenotypes from Evolutionary Pressures from a Highly Successful Pathogen

Zhang, Ying; Jacobs, William R.

doi:10.1002/9783527611614.ch15

Cited by 6 publications

(4 citation statements)

References 259 publications

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“…After 2 treatment days, the isoniazid stress signature was robustly induced in sputum, including mycolic acid biosynthesis genes ( fabD, acpM, kasA, kasB, accD6), an efflux gene (efpA), and an oxidative stressresponse gene (aphC). After 7 days, this signature was no longer upregulated, consistent with the known poor sterilizing activity of isoniazid [34].…”

Section: Expression Of Antibiotic-associated Genesmentioning

confidence: 58%

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Transcriptional Adaptation of Drug-tolerantMycobacterium tuberculosisDuring Treatment of Human Tuberculosis

et al. 2015

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Transcriptional patterns suggest that drug-tolerant bacilli in sputum are in a slow-growing, metabolically and synthetically downregulated state. Absence of the isoniazid stress signature in drug-tolerant bacilli indicates that physiological state influences drug responsiveness in vivo. These results identify novel drug targets that should aid in development of novel shorter tuberculosis treatment regimens.

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Section: Expression Of Antibiotic-associated Genesmentioning

confidence: 58%

“…target InhA causes low-level resistance [34], but, as in experimental models [11,13,30,46], inhA was not induced in drug-tolerant M. tuberculosis in sputum. Drug-tolerant M. tuberculosis had decreased expression of genes for fluoroquinolone targets GyrA and GyrB and bedaquiline target AtpE.…”

Section: Discussionmentioning

confidence: 84%

Transcriptional Adaptation of Drug-tolerantMycobacterium tuberculosisDuring Treatment of Human Tuberculosis

et al. 2015

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“…These technologies identify and characterize DR-TB infections based upon the presence or absence of known resistance-conferring mutations in the Mycobacterium tuberculosis genome (3)(4)(5). Unfortunately, the vast majority of rapid molecular DR-TB diagnostic tests, including line probe and microarray assays, rely on a closed set of mutations for resistance detection (6)(7)(8).…”

mentioning

confidence: 99%

Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape

Georghiou

Seifert

Catanzaro

et al. 2016

Antimicrob Agents Chemother

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f Molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (DR-TB). Sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. We performed pyrosequencing of seven Mycobacterium tuberculosis gene regions (katG, inhA, ahpC, rpoB, gyrA, rrs, and eis) for 1,128 clinical specimens from India, Moldova, and South Africa. We determined the frequencies of each mutation among drug-resistant and -susceptible specimens based on phenotypic drug susceptibility testing results and examined mutation distributions by country. The most common mutation among isoniazid-resistant (INH r ) specimens was the katG 315ACC mutation (87%). However, in the Eastern Cape, INH r specimens had a lower frequency of katG mutations (44%) and higher frequencies of inhA (47%) and ahpC (10%) promoter mutations. The most common mutation among rifampin-resistant (RIF r ) specimens was the rpoB 531TTG mutation (80%). The mutation was common in RIF r specimens in Mumbai (83%) and Moldova (84%) but not the Eastern Cape (17%), where the 516GTC mutation appeared more frequently (57%). The most common mutation among fluoroquinolone-resistant specimens was the gyrA 94GGC mutation (44%). The rrs 1401G mutation was found in 84%, 84%, and 50% of amikacin-resistant, capreomycin-resistant, and kanamycin (KAN)-resistant (KAN r ) specimens, respectively. The eis promoter mutation ؊12T was found in 26% of KAN r and 4% of KAN-susceptible (KAN s ) specimens. Inclusion of the ahpC and eis promoter gene regions was critical for optimal test sensitivity for the detection of INH resistance in the Eastern Cape and KAN resistance in Moldova. (This study has been registered at ClinicalTrials.gov under registration number NCT02170441.) I n 2014, an estimated 9.6 million people developed tuberculosis (TB), and 1.5 million people died of their infection (1). Although global TB incidence rates have fallen an average of 1.5% per year since 2000, the rise of drug-resistant TB (DR-TB) globally has complicated TB control efforts (1). The World Health Organization (WHO) estimates that as many as 1 in every 20 new, active TB infections is now drug resistant (1). One of the major roadblocks in combating this growing problem has been the lack of diagnostic technology for DR-TB. Current growth-based culture and drug susceptibility testing (DST) methods can take several weeks to months to yield results (2). While waiting on culture results, physicians are forced to treat their patients empirically, adjusting treatment regimens only once DST results become available. As a result, many undiagnosed DR-TB patients are being given medications that are ineffective, which amplifies resistance, increases the risk of mortality, and increases the risk of transmitting DR-TB infections in the community.Rapid molecular diagnostic assays for DR-TB have the p...

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“…Drug resistance (DR) in Mycobacterium tuberculosis is mainly due to single nucleotide polymorphisms (SNPs) in a small set of genes (6)(7)(8). The well-documented relationship(s) between phenotypic resistance and these resistance-conferring mutations has instigated a slow but transformative shift in DST methods from time-consuming cultured-based phenotypic methods to rapid sputum-based molecular DST (9).…”

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confidence: 99%

Laboratory Evaluation of a Lateral-Flow Cell for Molecular Detection of First-Line and Second-Line Antituberculosis Drug Resistance

et al. 2020

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Despite the WHO's call for universal drug susceptibility testing for all patients being evaluated for tuberculosis (TB), a lack of rapid diagnostic tests which can fully describe TB resistant patterns is a major challenge in ensuring that all persons diagnosed with drug-resistant TB are started on an appropriate treatment regime. We evaluated the accuracy of Akonni Biosystems XDR-TB TruArray® and Lateral Flow Cell (XDR-LFC), a novel multiplex assay to simultaneously detect mutations across seven genes that confer resistance to both first and second-line anti-TB drugs. The XDR-LFC includes 271 discrete three-dimensional gel elements with target-specific probes for identifying mutations in katG, inhA promoter, and ahpC promoter (isoniazid); rpoB (rifampin); gyrA (fluoroquinolones); rrs and eis promoter (kanamycin) and; rrs (capreomycin and amikacin). We evaluated XDR-LFC performance with 87 phenotypically and genotypically characterized clinical Mycobacterium tuberculosis (Mtb) isolates. Overall assay accuracy for mutation detection in specific genes was 98.6% for eis promoter and 100.0% for the genes katG, inhA promoter, ahpC promoter, rpoB, gyrA, and rrs. The sensitivity and specificity against phenotypic reference was 100% and 100% for isoniazid, 98.4% and 50% for rifampin (specificity increased to 100% once the strains with documented “low-level resistance mutations” in rpoB were excluded), 96.2% and 100% for fluoroquinolones, 92.6% and 100% for kanamycin, 93.9% and 97.4% for capreomycin and 80% and 100% for amikacin. The XDR-LFC solution appears to be a promising new tool for accurate detection of resistance to both first and second-line anti-TB drugs.

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Mechanisms of Drug Action, Drug Resistance and Drug Tolerance inMycobacterium tuberculosis: Expected Phenotypes from Evolutionary Pressures from a Highly Successful Pathogen

Cited by 6 publications

References 259 publications

Transcriptional Adaptation of Drug-tolerantMycobacterium tuberculosisDuring Treatment of Human Tuberculosis

Transcriptional Adaptation of Drug-tolerantMycobacterium tuberculosisDuring Treatment of Human Tuberculosis

Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape

Laboratory Evaluation of a Lateral-Flow Cell for Molecular Detection of First-Line and Second-Line Antituberculosis Drug Resistance

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