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Antibiotics
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Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs
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Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 32079

Special Issue Editor

Dr. Danila V. Zimenkov

E-Mail Website
Guest Editor
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
Interests: tuberculosis; drug resistance; microbial genetics; molecular assays; biochips; evolution; microbiology

Special Issue Information

Dear Colleagues,

The limited number of antituberculosis drugs and the quick rise of drug resistance are serious public health threats, demanding the development of novel drugs and regimens for successful treatment.

Research efforts are focused on searching for new targets and active compounds, evaluation of the repurposed drugs and adjusting doses of “old” drugs, studies of drug interaction, and determining effective regimens to achieve relapse-free cure. To reach the aim of personalized treatment that accounts for resistance, many molecular assays are under development complementing classical phenotypic methods.

The new era of massive whole-genome sequencing has resulted in a severe impact on our knowledge of the evolution of M. tuberculosis under the selective pressure of the therapy and host microenvironment. In addition to the identification of resistance-associated mutations and epidemiology surveillance, studies of microevolution have resulted in the identification of fitness compensatory mechanisms and the epistatic impact of genetic background on resistance development. The list of resistance determinants is expanding, and further analysis of resistant clinical strains is urgently needed to improve the reliability of molecular methods and our understanding of evolution.

This Special Issue seeks manuscript submissions that expand our understanding of drug-resistant tuberculosis, mechanisms, surveillance, and novel approaches to therapy. 

Dr. Danila V. Zimenkov
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tuberculosis
  • drug resistance
  • resistance determinants
  • genome organization
  • epidemiology and surveillance

Published Papers (12 papers)

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Research

22 pages, 6044 KiB  
Article
Development of New Antimycobacterial Sulfonyl Hydrazones and 4-Methyl-1,2,3-thiadiazole-Based Hydrazone Derivatives
by Violina T. Angelova, Tania Pencheva, Nikolay Vassilev, Elena K-Yovkova, Rositsa Mihaylova, Boris Petrov and Violeta Valcheva
Antibiotics 2022, 11(5), 562; https://doi.org/10.3390/antibiotics11050562 - 22 Apr 2022
Cited by 11 | Viewed by 2286
Abstract
Fifteen 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives 3a–d and sulfonyl hydrazones 5a–k were synthesized. They were characterized by 1H-NMR, 13C NMR, and HRMS. Mycobacterium tuberculosis strain H37Rv was used to assess their antimycobacterial activity. All compounds demonstrated significant minimum inhibitory [...] Read more.
Fifteen 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives 3a–d and sulfonyl hydrazones 5a–k were synthesized. They were characterized by 1H-NMR, 13C NMR, and HRMS. Mycobacterium tuberculosis strain H37Rv was used to assess their antimycobacterial activity. All compounds demonstrated significant minimum inhibitory concentrations (MIC) from 0.07 to 0.32 µM, comparable to those of isoniazid. The cytotoxicity was evaluated using the standard MTT-dye reduction test against human embryonic kidney cells HEK-293T and mouse fibroblast cell line CCL-1. 4-Hydroxy-3-methoxyphenyl substituted 1,2,3-thiadiazole-based hydrazone derivative 3d demonstrated the highest antimycobacterial activity (MIC = 0.0730 µM) and minimal associated cytotoxicity against two normal cell lines (selectivity index SI = 3516, HEK-293, and SI = 2979, CCL-1). The next in order were sulfonyl hydrazones 5g and 5k with MIC 0.0763 and 0.0716 µM, respectively, which demonstrated comparable minimal cytotoxicity. All compounds were subjected to ADME/Tox computational predictions, which showed that all compounds corresponded to Lipinski’s Ro5, and none were at risk of toxicity. The suitable scores of molecular docking performed on two crystallographic structures of enoyl-ACP reductase (InhA) provide promising insight into possible interaction with the InhA receptor. The 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives and sulfonyl hydrazones proved to be new classes of lead compounds having the potential of novel candidate antituberculosis drugs. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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10 pages, 667 KiB  
Article
Molecular Determinants of Ethionamide Resistance in Clinical Isolates of Mycobacterium tuberculosis
by Anastasia Ushtanit, Elena Kulagina, Yulia Mikhailova, Marina Makarova, Svetlana Safonova and Danila Zimenkov
Antibiotics 2022, 11(2), 133; https://doi.org/10.3390/antibiotics11020133 - 20 Jan 2022
Cited by 12 | Viewed by 3003
Abstract
Background: Ethionamide and prothionamide are now included in group C of the WHO recommended drugs for the treatment of tuberculosis resistant to rifampicin and multidrug-resistant tuberculosis. The clinical relevance of ethionamide and prothionamide has increased with the wide spread of resistant tuberculosis. Methods: [...] Read more.
Background: Ethionamide and prothionamide are now included in group C of the WHO recommended drugs for the treatment of tuberculosis resistant to rifampicin and multidrug-resistant tuberculosis. The clinical relevance of ethionamide and prothionamide has increased with the wide spread of resistant tuberculosis. Methods: We retrospectively analyzed 349 clinical isolates obtained between 2016 and 2020. The susceptibility to ethionamide was tested using both the BactecTM MGITTM 960 system and the SensititreTM MYCOTB plate. Results: The MIC of ethionamide increases with the total resistance of the isolates in a row from susceptible to XDR strains. A significant part of the isolates have a MIC below the breakpoint: 25%, 36%, and 50% for XDR, pre-XDR, and MDR strains. Sensitivity and specificity of detection of mutations were 96% and 86% using MGIT resistance as a reference. Conclusions: Phenotypic methods for testing ethionamide are imperfectly correlated, and the isolates with MIC of 5 mg/L have the intermediate resistance. A significant proportion of resistant TB cases are susceptible and eligible for ethionamide treatment. Resistance could be explained using only analysis of loci ethA, PfabG1, and inhA for most isolates in the Moscow region. The promoter mutation PfabG1 c(-15)t predicts resistance to ethionamide with high specificity but low sensitivity. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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10 pages, 809 KiB  
Article
Genetic Profile of Linezolid-Resistant M. tuberculosis Clinical Strains from Moscow
by Anastasia Ushtanit, Yulia Mikhailova, Alexandra Lyubimova, Marina Makarova, Svetlana Safonova, Alexey Filippov, Sergey Borisov and Danila Zimenkov
Antibiotics 2021, 10(10), 1243; https://doi.org/10.3390/antibiotics10101243 - 13 Oct 2021
Cited by 4 | Viewed by 1680
Abstract
Background: Linezolid, bedaquiline, and newer fluoroquinolones are currently placed as priority Group A drugs for the treatment of drug-resistant tuberculosis. The number of reported linezolid-resistant clinical strains is still low, and the correlation of molecular determinants with phenotype is not perfect. Methods: We [...] Read more.
Background: Linezolid, bedaquiline, and newer fluoroquinolones are currently placed as priority Group A drugs for the treatment of drug-resistant tuberculosis. The number of reported linezolid-resistant clinical strains is still low, and the correlation of molecular determinants with phenotype is not perfect. Methods: We determined the linezolid MICs for clinical isolates from the Moscow region and identified mutations in rplC and rrl genes. Results: All 16 linezolid-resistant isolates had previously reported mutations in the rplC or rrl loci, and 13 of them bore a RplC C154R substitution. Detection of this substitution in a heteroresistant state was not successful, probably, due to the more stable DNA secondary structure of the mutated fragment, which precludes its amplification in mixes with the wild-type DNA. Strains with an rplC mutation had higher linezolid MIC compared to isolates with rrl mutations. Conclusions: Linezolid resistance mostly emerged during treatment with the latest regimen. Three primary cases with linezolid resistance question the possible transmission of totally drug-resistant tuberculosis in the Moscow region, which demands further investigation. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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14 pages, 1881 KiB  
Article
The Epistatic Landscape of Antibiotic Resistance of Different Clades of Mycobacterium tuberculosis
by Dillon Muzondiwa, Hleliwe Hlanze and Oleg N. Reva
Antibiotics 2021, 10(7), 857; https://doi.org/10.3390/antibiotics10070857 - 15 Jul 2021
Cited by 8 | Viewed by 2796
Abstract
Drug resistance (DR) remains a global challenge in tuberculosis (TB) control. In order to develop molecular-based diagnostic methods to replace the traditional culture-based diagnostics, there is a need for a thorough understanding of the processes that govern TB drug resistance. The use of [...] Read more.
Drug resistance (DR) remains a global challenge in tuberculosis (TB) control. In order to develop molecular-based diagnostic methods to replace the traditional culture-based diagnostics, there is a need for a thorough understanding of the processes that govern TB drug resistance. The use of whole-genome sequencing coupled with statistical and computational methods has shown great potential in unraveling the complexity of the evolution of DR-TB. In this study, we took an innovative approach that sought to determine nonrandom associations between polymorphic sites in Mycobacterium tuberculosis (Mtb) genomes. Attributable risk statistics were applied to identify the epistatic determinants of DR in different clades of Mtb and the possible evolutionary pathways of DR development. It was found that different lineages of Mtb exploited different evolutionary trajectories towards multidrug resistance and compensatory evolution to reduce the DR-associated fitness cost. Epistasis of DR acquisition is a new area of research that will aid in the better understanding of evolutionary biological processes and allow predicting upcoming multidrug-resistant pathogens before a new outbreak strikes humanity. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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12 pages, 2464 KiB  
Article
Molecular Analysis of Streptomycin Resistance Genes in Clinical Strains of Mycobacterium tuberculosis and Biocomputational Analysis of the MtGidB L101F Variant
by Álvaro Rodríguez-García, Rosa E. Mares-Alejandre, Patricia L. A. Muñoz-Muñoz, Samuel Ruvalcaba-Ruiz, Ricardo A. González-Sánchez, Johanna Bernáldez-Sarabia, Samuel G. Meléndez-López, Alexei F. Licea-Navarro and Marco A. Ramos-Ibarra
Antibiotics 2021, 10(7), 807; https://doi.org/10.3390/antibiotics10070807 - 02 Jul 2021
Cited by 6 | Viewed by 2231
Abstract
Globally, tuberculosis (TB) remains a prevalent threat to public health. In 2019, TB affected 10 million people and caused 1.4 million deaths. The major challenge for controlling this infectious disease is the emergence and spread of drug-resistant Mycobacterium tuberculosis, the causative agent [...] Read more.
Globally, tuberculosis (TB) remains a prevalent threat to public health. In 2019, TB affected 10 million people and caused 1.4 million deaths. The major challenge for controlling this infectious disease is the emergence and spread of drug-resistant Mycobacterium tuberculosis, the causative agent of TB. The antibiotic streptomycin is not a current first-line anti-TB drug. However, WHO recommends its use in patients infected with a streptomycin-sensitive strain. Several mutations in the M. tuberculosisrpsL, rrs and gidB genes have proved association with streptomycin resistance. In this study, we performed a molecular analysis of these genes in clinical isolates to determine the prevalence of known or novel mutations. Here, we describe the genetic analysis outcome. Furthermore, a biocomputational analysis of the MtGidB L101F variant, the product of a novel mutation detected in gidB during molecular analysis, is also reported as a theoretical approach to study the apparent genotype-phenotype association. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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9 pages, 283 KiB  
Article
Rapid Molecular Diagnosis of Tuberculosis and Its Resistance to Rifampicin and Isoniazid with Automated MDR/MTB ELITe MGB® Assay
by Vichita Ok, Alexandra Aubry, Florence Morel, Isabelle Bonnet, Jérôme Robert and Wladimir Sougakoff
Antibiotics 2021, 10(7), 797; https://doi.org/10.3390/antibiotics10070797 - 30 Jun 2021
Cited by 1 | Viewed by 1866
Abstract
The MDR/MTB ELITe MGB® kit (ELITech) carried on the ELITe InGenius® platform is a new real-time PCR assay allowing automated extraction and detection of DNA of the Mycobacterium tuberculosis complex (MTB) and mutations in the rpoB and katG genes and inhA [...] Read more.
The MDR/MTB ELITe MGB® kit (ELITech) carried on the ELITe InGenius® platform is a new real-time PCR assay allowing automated extraction and detection of DNA of the Mycobacterium tuberculosis complex (MTB) and mutations in the rpoB and katG genes and inhA promoter region (pro-inhA) associated to resistance to rifampicin and isoniazid, the two markers of multidrug-resistant TB (MDR). We assessed the performances of the test on a collection of strains (n = 54) and a set of clinical samples (n = 242) from routine practice, comparatively to TB diagnosis and genotypic drug susceptibility testing (gDST) as references. Regarding the 242 clinical samples, the sensitivity and specificity of MTB detection by ELITe were 90.9% and 97.5%, respectively. For the detection of resistance-conferring mutations on positive clinical samples, we observed perfect agreement with gDST for katG and pro-inhA (κ = 1.0) and two discordant results for rpoB (κ = 0.82). Considering the 54 cultured strains, very good agreement with gDST was observed for the detection of the 25 distinct mutations in rpoB, katG, and pro-inhA, (κ = 0.95, 0.88, and 0.95, respectively). In conclusion, the automated MDR/MTB ELITe MGB® assay shows great promise and appears to be a valuable tool for rapid detection of pre-MDR- and MDR-TB directly from clinical specimens. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
14 pages, 3023 KiB  
Article
Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness
by Prakruti S. Rao, Christopher C. Moore, Amir A. Mbonde, Edwin Nuwagira, Patrick Orikiriza, Dan Nyehangane, Mohammad H. Al-Shaer, Charles A. Peloquin, Jean Gratz, Suporn Pholwat, Rinah Arinaitwe, Yap Boum, Juliet Mwanga-Amumpaire, Eric R. Houpt, Leonid Kagan, Scott K. Heysell and Conrad Muzoora
Antibiotics 2021, 10(6), 739; https://doi.org/10.3390/antibiotics10060739 - 18 Jun 2021
Cited by 11 | Viewed by 3196
Abstract
Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, [...] Read more.
Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, with and without meningitis, in Mbarara, Uganda that were starting first-line anti-TB therapy. Serum was collected two weeks after enrollment at 1-, 2-, 4-, and 6-h post-dose and drug concentrations quantified by validated LC-MS/MS methods. Non-compartmental analyses were used to determine total drug exposure, and population pharmacokinetic modeling and simulations were performed to determine optimal dosages. Eighty-one participants were enrolled. Forty-nine completed pharmacokinetic testing: 18 (22%) died prior to testing, 13 (16%) were lost to follow-up and one had incomplete testing. Isoniazid had the lowest serum attainment, with only 4.1% achieving a target exposure over 24 h (AUC0–24) of 52 mg·h/L despite appropriate weight-based dosing. Simulations to reach target AUC0–24 found necessary doses of rifampin of 1800 mg, pyrazinamide of 2500–3000 mg, and for isoniazid 900 mg or higher. Given the high case fatality ratio of TB-related critical illness in this population, an early higher dose anti-TB therapy should be trialed. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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8 pages, 794 KiB  
Communication
Cross-Contamination versus Outbreak: Pre-XDR Mycobacterial Strains Confirmed by Whole-Genome Sequencing
by Jee Youn Oh, Kyung Ho Park, Jisoon Lee, Donghyeok Kim, Kwang Hyuk Seok, In-Hwan Oh and Seung Heon Lee
Antibiotics 2021, 10(3), 297; https://doi.org/10.3390/antibiotics10030297 - 12 Mar 2021
Cited by 2 | Viewed by 1726
Abstract
Whole-genome sequencing (WGS) is promising for the quality control of laboratory facilities for Mycobacterium tuberculosis (MTB) strains. We describe the clinical and laboratory characteristics of false positive versus true positive MTB cultures based on WGS, which were experienced in a real clinical setting. [...] Read more.
Whole-genome sequencing (WGS) is promising for the quality control of laboratory facilities for Mycobacterium tuberculosis (MTB) strains. We describe the clinical and laboratory characteristics of false positive versus true positive MTB cultures based on WGS, which were experienced in a real clinical setting. Strain harvest and DNA extraction from seven isolates from pre-extensive drug-resistant (pre-XDR) TB patients transferred to the Korea University Ansan Hospital were performed, and epidemiologic links and clinical information, including the phenotypic drug susceptibility test (pDST), were investigated. WGS was performed using Ion GeneStudio with an ION530tm chip (average sequencing depth, ~100-fold). In the phylogenetic tree, identical and different strains were distributed separately. Five of the seven isolates were identical; the remaining two isolates differed from the others. The images of the referred pre-XDR-TB patients with false positive MTB that were analyzed were of regions close to old TB scars. Further, the results of WGS gene mutation analysis for ethambutol, streptomycin, and fluoroquinolone resistance in all six patients were not concordant with the pDST results. WGS and clinical information were useful in differentiating laboratory cross-contamination from true positive TB, thereby avoiding the unnecessary treatment of false positive patients and delay in treating true positive TB patients, with reliable genotypic drug resistance results. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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10 pages, 900 KiB  
Article
Increase in Tuberculosis Diagnostic Delay during First Wave of the COVID-19 Pandemic: Data from an Italian Infectious Disease Referral Hospital
by Francesco Di Gennaro, Gina Gualano, Laura Timelli, Pietro Vittozzi, Virginia Di Bari, Raffaella Libertone, Carlotta Cerva, Luigi Pinnarelli, Carla Nisii, Stefania Ianniello, Silvia Mosti, Nazario Bevilacqua, Fabio Iacomi, Annalisa Mondi, Simone Topino, Delia Goletti, Francesco Vaia, Giuseppe Ippolito, Enrico Girardi and Fabrizio Palmieri
Antibiotics 2021, 10(3), 272; https://doi.org/10.3390/antibiotics10030272 - 08 Mar 2021
Cited by 61 | Viewed by 4681
Abstract
Background: The WHO advised that the impact of COVID-19 pandemic on TB services was estimated to be dramatic due to the disruption of TB services. Methods: A retrospective data collection and evaluation was conducted to include all the patients hospitalized for TB at [...] Read more.
Background: The WHO advised that the impact of COVID-19 pandemic on TB services was estimated to be dramatic due to the disruption of TB services. Methods: A retrospective data collection and evaluation was conducted to include all the patients hospitalized for TB at INMI from 9 March to 31 August 2020 (lockdown period and three months thereafter). For the purpose of the study, data from patients hospitalized in the same period of 2019 were also collected. Results: In the period of March–August 2019, 201 patients were hospitalized with a diagnosis of TB, while in the same period of 2020, only 115 patients, with a case reduction of 43%. Patients with weight loss, acute respiratory failure, concurrent extrapulmonary TB, and higher Timika radiographic scores were significantly more frequently hospitalized during 2020 vs. 2019. The median patient delay was 75 days (IQR: 40–100) in 2020 compared to 30 days (IQR: 10–60) in 2019 (p < 0.01). Diagnostic delays in 2020 remain significant in the multiple logistic model (AOR = 6.93, 95%CI: 3.9–12.3). Conclusions: Our experience suggests that COVID-19 pandemic had an impact on TB patient care in terms of higher diagnostic delay, reduction in hospitalization, and a greater severity of clinical presentations. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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12 pages, 584 KiB  
Article
Genomic Variations in Drug Resistant Mycobacterium tuberculosis Strains Collected from Patients with Different Localization of Infection
by Ekaterina Chernyaeva, Mikhail Rotkevich, Ksenia Krasheninnikova, Alla Lapidus, Dmitrii E. Polev, Natalia Solovieva, Viacheslav Zhuravlev, Piotr Yablonsky and Stephen J. O’Brien
Antibiotics 2021, 10(1), 27; https://doi.org/10.3390/antibiotics10010027 - 31 Dec 2020
Cited by 3 | Viewed by 2491
Abstract
Mycobacterium tuberculosis is a highly studied pathogen due to public health importance. Despite this, problems like early drug resistance, diagnostics and treatment success prediction are still not fully resolved. Here, we analyze the incidence of point mutations widely used for drug resistance detection [...] Read more.
Mycobacterium tuberculosis is a highly studied pathogen due to public health importance. Despite this, problems like early drug resistance, diagnostics and treatment success prediction are still not fully resolved. Here, we analyze the incidence of point mutations widely used for drug resistance detection in laboratory practice and conduct comparative analysis of whole-genome sequence (WGS) for clinical M. tuberculosis strains collected from patients with pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (XPTB) localization. A total of 72 pulmonary and 73 extrapulmonary microbiologically characterized M. tuberculosis isolates were collected from patients from 2007 to 2014 in Russia. Genomic DNA was used for WGS and obtained data allowed identifying major mutations known to be associated with drug resistance to first-line and second-line antituberculous drugs. In some cases previously described mutations were not identified. Using genome-based phylogenetic analysis we identified M. tuberculosis substrains associated with distinctions in the occurrence in PTB vs. XPTB cases. Phylogenetic analyses did reveal M. tuberculosis genetic substrains associated with TB localization. XPTB was associated with Beijing sublineages Central Asia (Beijing CAO), Central Asia Clade A (Beijing A) and 4.8 groups, while PTB localization was associated with group LAM (4.3). Further, the XPTB strain in some cases showed elevated drug resistance patterns relative to PTB isolates. HIV was significantly associated with the development of XPTB in the Beijing B0/W148 group and among unclustered Beijing isolates. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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10 pages, 407 KiB  
Article
Identification of Mutations Conferring Tryptanthrin Resistance to Mycobacterium smegmatis
by Svetlana G. Frolova, Ksenia M. Klimina, Ravinder Kumar, Aleksey A. Vatlin, Deepak B. Salunke, Pravin Kendrekar, Valery N. Danilenko and Dmitry A. Maslov
Antibiotics 2021, 10(1), 6; https://doi.org/10.3390/antibiotics10010006 - 23 Dec 2020
Cited by 10 | Viewed by 2644
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a global burden, responsible for over 1 million deaths annually. The emergence and spread of drug-resistant M. tuberculosis strains (MDR-, XDR- and TDR-TB) is the main challenge in global TB-control, requiring the development of novel [...] Read more.
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a global burden, responsible for over 1 million deaths annually. The emergence and spread of drug-resistant M. tuberculosis strains (MDR-, XDR- and TDR-TB) is the main challenge in global TB-control, requiring the development of novel drugs acting on new biotargets, thus able to overcome the drug-resistance. Tryptanthrin is a natural alkaloid, with great therapeutic potential due to its simple way of synthesis and wide spectrum of biological activities including high bactericidal activity on both drug-susceptible and MDR M. tuberculosis strains. InhA was suggested as the target of tryptanthrins by in silico modeling, making it a promising alternative to isoniazid, able to overcome drug resistance provided by katG mutations. However, neither the mechanism of action of tryptanthrin nor the mechanism of resistance to tryptanthrins was ever confirmed in vitro. We show that the MmpS5-MmpL5 efflux system is able to provide resistance to tryptanthrins using an in-house test-system. Comparative genomic analysis of spontaneous tryptanthrin-resistant M. smegmatis mutants showed that mutations in MSMEG_1963 (EmbR transcriptional regulator) lead to a high-level resistance, while those in MSMEG_5597 (TetR transcriptional regulator) to a low-level one. Mutations in an MFS transporter gene (MSMEG_4427) were also observed, which might be involved in providing a basal level of tryptanthrins-resistance. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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9 pages, 615 KiB  
Article
Genetic Variation Putatively Associated with Mycobacterium tuberculosis Resistance to Perchlozone, a New Thiosemicarbazone: Clues from Whole Genome Sequencing and Implications for Treatment of Multidrug-Resistant Tuberculosis
by Igor Mokrousov, Anna Vyazovaya, Gulnora Akhmedova, Natalia Solovieva, Eugeni Turkin and Viacheslav Zhuravlev
Antibiotics 2020, 9(10), 669; https://doi.org/10.3390/antibiotics9100669 - 03 Oct 2020
Cited by 4 | Viewed by 2091
Abstract
Perchlozone ([PCZ] 4-thioureido-iminomethylpyridinium perchlorate) is a new thiosemicarbazone approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in Russia and some other countries. The ethA and hadABC mutations may confer PCZ resistance. At the same time, ethA mutations are known to mediate resistance to [...] Read more.
Perchlozone ([PCZ] 4-thioureido-iminomethylpyridinium perchlorate) is a new thiosemicarbazone approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in Russia and some other countries. The ethA and hadABC mutations may confer PCZ resistance. At the same time, ethA mutations are known to mediate resistance to ethionamide (ETH) and prothionamide (PTH). We aimed to study the genetic variation underlying Mycobacterium tuberculosis resistance to PCZ through whole genome sequencing (WGS) of consecutive isolates recovered during long-term treatment. This prospective study included patients admitted in 2018–2019 to the regional tuberculosis dispensary, Kaliningrad, Russia, whose treatment regimen included PCZ. Multiple M. tuberculosis isolates were recovered during PCZ treatment, and the bacterial DNA was subjected to WGS followed by bioinformatics analysis. We identified mutations in the genes putatively associated with PCZ resistance, ethA, and hadA. The most frequent one was a frameshift ethA 106 GA > G (seven of nine patients) and most of the other mutations were also likely present before PCZ treatment. In one patient, a frameshift mutation ethA 702 CT > C emerged after six months of PCZ treatment. A frequent presence of cross-resistance mutations to PCZ and ETH/PTH should be taken into consideration when PCZ is included in the treatment regimen of MDR-TB patients. Full article
(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)
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