scholarly journals Drug Resistance Mechanisms in Tuberculosis

2020 ◽  
Author(s):  
Lanfranco Fattorini ◽  
Angelo Iacobino ◽  
Federico Giannoni
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Drug Distribution ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Diagnostic Methods ◽  
Drug Resistant ◽  
Resistance Development ◽  
Intrinsic Drug Resistance ◽  
Incident Cases

The increased incidence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two highly bactericidal first-line drugs, is a major concern for tuberculosis (TB) control. The worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, is causing increasing concern. In this view, it is important to continuously update the knowledge on the mechanisms involved in the development of drug-resistant TB. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. Here, a piece of information on the interplay of these factors is provided, to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods.

scholarly journals Drug-Resistant Tuberculosis 2020: Where We Stand

2020 ◽  
Vol 10 (6) ◽  
pp. 2153 ◽  
Author(s):  
Angelo Iacobino ◽  
Lanfranco Fattorini ◽  
Federico Giannoni
Keyword(s):  
Molecular Mechanisms ◽  
Drug Distribution ◽  
Multidrug Resistant ◽  
Diagnostic Methods ◽  
World Health ◽  
Drug Resistant ◽  
Comprehensive Overview ◽  
Resistant Tuberculosis ◽  
Health Organization ◽  
Incident Cases

The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods.

scholarly journals Targeting the bacterial SOS response for new antimicrobial agents: drug targets, molecular mechanisms and inhibitors

2021 ◽  
Author(s):  
Thomas Lanyon-Hogg
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Structure And Function ◽  
Drug Resistant ◽  
Target Validation ◽  
Sos Pathway ◽  
And Function

Antimicrobial resistance is a pressing threat to global health, with multidrug-resistant pathogens becoming increasingly prevalent. The bacterial SOS pathway functions in response to DNA damage that occurs during infection, initiating several pro-survival and resistance mechanisms, such as DNA repair and hypermutation. This makes SOS pathway components potential targets that may combat drug-resistant pathogens and decrease resistance emergence. This review discusses the mechanism of the SOS pathway; the structure and function of potential targets AddAB, RecBCD, RecA and LexA; and efforts to develop selective small-molecule inhibitors of these proteins. These inhibitors may serve as valuable tools for target validation and provide the foundations for desperately needed novel antibacterial therapeutics.

Assessing the utility of three TaqMan probes for the diagnosis of tuberculosis and resistance to rifampin and isoniazid in Veracruz, México

2012 ◽  
Vol 58 (3) ◽  
pp. 318-325 ◽  
Author(s):  
Roberto Zenteno-Cuevas ◽  
Betzaida Cuevas-Cordoba ◽  
Antonio Enciso ◽  
Leonor Enciso ◽  
Aremy Cuellar
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Rpob Gene ◽  
Diagnostic Value ◽  
Multidrug Resistant ◽  
Molecular Probes ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Taqman Probes ◽  
Resistant Tuberculosis

Mutations at codons 526 and 531 in the rpoB gene and at 315 in the katG gene are considered diagnostic markers for resistance to rifampin and isoniazid in tuberculosis. The aim of this study was to design and evaluate three TaqMan probes for the identification of these mutations in 138 respiratory samples positive for acid-fast bacilli, and 32 clinical isolates from a region with considerable levels of drug resistance. The specificities of the probes for the diagnosis of resistance to both drugs were 100%; however, the sensitivities were calculated to be 50% for isoniazid and 56% for rifampin. DNA sequencing of rpoB and katG; and the spoligotyping assay of the clinical isolates, confirmed the diversity of the mutations and the presence of 11 spoligotypes with a shared international type and eight unique spoligotypes. Analysis of the respiratory samples identified 22 (16%) as drug-resistant and 4 (3%) as multidrug-resistant tuberculosis. The diagnostic value of the TaqMan probes was compromised by the diversity of mutations found in the clinical isolates. This highlights the need for better understanding of the molecular mechanisms responsible for drug resistance prior to the use of molecular probes, especially in regions with significant levels of drug-resistant tuberculosis.

scholarly journals Programmable Base Editing in Mycobacterium tuberculosis Using an Engineered CRISPR RNA-Guided Cytidine Deaminase

2021 ◽  
Vol 3 ◽  
Author(s):  
Xin-Yuan Ding ◽  
Si-Shang Li ◽  
Yi-Man Geng ◽  
Mei-Yi Yan ◽  
Guo-Bao Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Molecular Mechanisms ◽  
Cytidine Deaminase ◽  
Point Mutations ◽  
Treatment Strategies ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Bacterial Physiology ◽  
Base Editing

Multidrug-resistant Mycobacterium tuberculosis (Mtb) infection seriously endangers global human health, creating an urgent need for new treatment strategies. Efficient genome editing tools can facilitate identification of key genes and pathways involved in bacterial physiology, pathogenesis, and drug resistance mechanisms, and thus contribute to the development of novel treatments for drug-resistant tuberculosis. Here, we report a two-plasmid system, MtbCBE, used to inactivate genes and introduce point mutations in Mtb. In this system, the assistant plasmid pRecX-NucSE107A expresses RecX and NucSE107A to repress RecA-dependent and NucS-dependent DNA repair systems, and the base editor plasmid pCBE expresses a fusion protein combining cytidine deaminase APOBEC1, Cas9 nickase (nCas9), and uracil DNA glycosylase inhibitor (UGI). Together, the two plasmids enabled efficient G:C to A:T base pair conversion at desired sites in the Mtb genome. The successful development of a base editing system will facilitate elucidation of the molecular mechanisms underlying Mtb pathogenesis and drug resistance and provide critical inspiration for the development of base editing tools in other microbes.

scholarly journals Analysis of drug resistance and mutation profiles in Mycobacterium tuberculosis isolates in a surveillance site in Beijing, China

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098493
Author(s):  
Jie Zhang ◽  
Yixuan Ren ◽  
Liping Pan ◽  
Junli Yi ◽  
Tong Guan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Testing ◽  
Multidrug Resistant ◽  
High Rate ◽  
Drug Resistant ◽  
Surveillance Site ◽  
Mdr Tb ◽  
Previously Treated Patients ◽  
Beijing China

Objective This study analyzed drug resistance and mutations profiles in Mycobacterium tuberculosis isolates in a surveillance site in Huairou District, Beijing, China. Methods The proportion method was used to assess drug resistance profiles for four first-line and seven second-line anti-tuberculosis (TB) drugs. Molecular line probe assays were used for the rapid detection of resistance to rifampicin (RIF) and isoniazid (INH). Results Among 235 strains of M. tuberculosis, 79 (33.6%) isolates were resistant to one or more drugs. The isolates included 18 monoresistant (7.7%), 19 polyresistant (8.1%), 28 RIF-resistant (11.9%), 24 multidrug-resistant (MDR) (10.2%), 7 pre-extensively drug-resistant (XDR, 3.0%), and 2 XDR strains (0.9%). A higher rate of MDR-TB was detected among previously treated patients than among patients with newly diagnosed TB (34.5% vs. 6.8%). The majority (62.5%) of RIF-resistant isolates exhibited a mutation at S531L in the DNA-dependent RNA polymerase gene. Meanwhile, 62.9% of INH-resistant isolates carried a mutation at S315T1 in the katG gene. Conclusion Our results confirmed the high rate of drug-resistant TB, especially MDR-TB, in Huairou District, Beijing, China. Therefore, detailed drug testing is crucial in the evaluation of MDR-TB treatment.

scholarly journals Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

2021 ◽  
Vol 11 (5) ◽  
pp. 663
Author(s):  
Elena D. Bazhanova ◽  
Alexander A. Kozlov ◽  
Anastasia V. Litovchenko
Keyword(s):  
Drug Resistance ◽  
Premature Death ◽  
Resistance Mechanisms ◽  
Biomedical Literature ◽  
Drug Resistant ◽  
Psychological Consequences ◽  
Text Documents ◽  
Neural Connections ◽  
Inflammatory Processes ◽  
Drug Resistant Epilepsy

Epilepsy is a chronic neurological disorder characterized by recurring spontaneous seizures. Drug resistance appears in 30% of patients and it can lead to premature death, brain damage or a reduced quality of life. The purpose of the study was to analyze the drug resistance mechanisms, especially neuroinflammation, in the epileptogenesis. The information bases of biomedical literature Scopus, PubMed, Google Scholar and SciVerse were used. To obtain full-text documents, electronic resources of PubMed Central and Research Gate were used. The article examines the recent research of the mechanisms of drug resistance in epilepsy and discusses the hypotheses of drug resistance development (genetic, epigenetic, target hypothesis, etc.). Drug-resistant epilepsy is associated with neuroinflammatory, autoimmune and neurodegenerative processes. Neuroinflammation causes immune, pathophysiological, biochemical and psychological consequences. Focal or systemic unregulated inflammatory processes lead to the formation of aberrant neural connections and hyperexcitable neural networks. Inflammatory mediators affect the endothelium of cerebral vessels, destroy contacts between endothelial cells and induce abnormal angiogenesis (the formation of “leaky” vessels), thereby affecting the blood–brain barrier permeability. Thus, the analysis of pro-inflammatory and other components of epileptogenesis can contribute to the further development of the therapeutic treatment of drug-resistant epilepsy.

Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae

2021 ◽  
Vol 70 (4) ◽  
Author(s):  
Balaram Khamari ◽  
Prakash Kumar ◽  
Bulagonda Eswarappa Pradeep
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Treatment Options ◽  
Strong Association ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Content Type ◽  
Link Type

Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options. Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited. Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae . Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR. Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla PER-1, bla NDM-1, bla OXA-48, ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible. Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae , harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.

scholarly journals Genotypes of Mycobacterium tuberculosis isolates circulating in Shaanxi Province, China

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0242971
Author(s):  
Yan Li ◽  
Yu Pang ◽  
Tianhua Zhang ◽  
Xiaoping Xian ◽  
Jian Yang ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Shaanxi Province ◽  
Drug Resistant ◽  
Beijing Family ◽  
Tuberculosis Patients ◽  
Smear Positive Pulmonary Tuberculosis ◽  
Discriminatory Index

Objectives The prevalence of drug-resistant TB in Shaanxi Province is higher than other areas. This study was aimed to investigate the genetic diversity and epidemiology of Mycobacterium tuberculosis clinical strains in Shaanxi Province, China. Methods From January to December 2016, a total of 298 Mycobacterium tuberculosis clinical isolates from smear-positive pulmonary tuberculosis patients were genotyped by Mcspoligotyping and 15-locus VNTR. Results We found that the Beijing family strains was the most prominent family(81.54%, 243/298). Other family strains included T family(9.06%, 27/298), U family(0.67%, 2/298), LAM9 family(0.34%, 1/298) and Manu family(0.34%, 1/298). The rates of multidrug-resistant (MDR) M.Tuberculosis, age, type of case and education between Beijing and non-Beijing family strains were not statistically different, while the distribution in the three different regions among these was statistically significant. VNTR results showed that strains were classified into 280 genotypes, and 33 (11.07%) strains could be grouped into 14 clusters. 11 of the 15-VNTR loci were highly or moderately discriminative according to the Hunter-Gaston discriminatory index. Conclusions We concluded that the Beijing family genotype was the most prevalent genotype and 15-locus VNTR typing might be suitable for genotyping of M. tuberculosis in Shaanxi Province. There was less association between Beijing family genotypes and drug resistance in our study area.

scholarly journals Primary HIV drug resistance among newly HIV type-1 diagnosed patients in St. Petersburg

2021 ◽  
Vol 13 (1) ◽  
pp. 70-79
Author(s):  
Thierry Ingabire ◽  
A. V. Semenov ◽  
E. V. Esaulenko ◽  
E. B. Zueva ◽  
A. N. Schemelev ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Direct Sequencing ◽  
Population Level ◽  
Multidrug Resistant ◽  
Antiretroviral Drugs ◽  
Drug Resistant ◽  
Resistant Virus ◽  
Primary Drug Resistance ◽  
Hiv 1

There is concern that the widespread use of antiretroviral drugs (ARV) to treat human immunodeficiency virus 1 (HIV-1) infection may result in the emergence of transmission of drug-resistant virus among persons newly infected with HIV-1. Russia is one of a growing number of countries in the world where drug-resistant HIV is becoming a serious health problem because it has the potential to compromise the efficacy of antiretroviral therapy (ART) at the population level.Materials and methods. We performed a genetic analysis of the HIV-1 plasma derived pol gene among the newly diagnosed ART-naïve HIV-1 infected patients during the period from November 2018 to October 2019 in the St. Petersburg Clinical Infectious Diseases Hospital named after S.P. Botkin. We used reverse transcriptase polymerase chain reaction (RT-PCR) followed by direct sequencing of PCR products to determine the prevalence of primary drug resistance (PDR) conferring mutations. HIV-1 genotypes were determined by phylogenetic analysis.Results. The predominant HIV-1 subtype was A1 (87.2%), followed by B (11.8%) and CRF06_cpx (1%). The overall prevalence of PDR was 11%. Virus with known resistance-conferring mutations to any nucleoside reverse transcriptase inhibitors (NRTIs) was found in 8 individuals, to any non NRTIs in 5 subjects, and to any protease inhibitors in 1 case. Multidrug-resistant virus was identified in 2 individuals (2%).Conclusion. The distribution of HIV-1 genotypes in St. Petersburg, Russia is diverse. The emerging prevalence of PDR in ART-naïve patients demonstrates the significance of constant monitoring due to the challenges it presents towards treatment.

scholarly journals Angiogenesis as a Therapeutic Target in Endometriosis

2014 ◽  
Vol 27 (4) ◽  
pp. 489 ◽  
Author(s):  
Dusan Djokovic ◽  
Carlos Calhaz-Jorge
Keyword(s):  
Drug Resistance ◽  
Literature Search ◽  
Molecular Mechanisms ◽  
Management Strategies ◽  
Angiogenesis Inhibitors ◽  
Resistance Development ◽  
Key Factor ◽  
Successful Establishment ◽  
Multimodal Management ◽  
Gynecological Disorder

<p><strong>Introduction:</strong> Angiogenesis is a key factor for the successful establishment and growth of endometriotic lesions.<br /><strong>Material and Methods:</strong> We performed a literature search in PubMed and reviewed the most pertinent studies published until January 2014 and focused on the endometriosis-associated angiogenesis and/or anti-angiogenic strategies for the treatment of this gynecological disorder.<br /><strong>Results:</strong> The present review provides a concise summary of the known molecular mechanisms that promote vascularization of endometriotic lesions and may serve as potential therapeutic targets. We also present a systematic overview of the inclusive and exclusive anti-angiogenic agents that have been already studied in cell cultures, animal models and/or endometriosis patients.<br /><strong>Discussion and Conclusion:</strong> The integration of anti-angiogenic approaches in the multimodal management strategies for endometriosis patients will be conditioned by the outcomes of future assessments regarding the effectiveness of such treatments, the risk of drug resistance development and the incidence of unacceptable side effects.<br /><strong>Keywords:</strong> Angiogenesis Inhibitors/therapeutic use; Endometriosis/drug therapy.</p>

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