scholarly journals Mycobacterium tuberculosis H2S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1285
Author(s):  
Tafara T. R. Kunota ◽  
Md. Aejazur Rahman ◽  
Barry E. Truebody ◽  
Jared S. Mackenzie ◽  
Vikram Saini ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Routine Laboratory ◽  
Central Metabolism ◽  
Effector Molecule ◽  
Cytochrome Bd ◽  
Endogenous Production ◽  
Laboratory Culturing ◽  
H2s Production

H2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H2S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H2S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H2S, whereas H2S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H2S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H2S production, suggesting the involvement of multiple genes in H2S production. We identified endogenous H2S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H2S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and it functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H2S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.

scholarly journals Mycobacterium tuberculosis H2S functions as a sink to modulate central metabolism, bioenergetics, and drug susceptibility

2021 ◽  
Author(s):  
Tafara T. R. Kunota ◽  
Md. Aejazur Rahman ◽  
Barry E. Truebody ◽  
Jared Stuart Mackenzie ◽  
Vikram Saini ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Routine Laboratory ◽  
Central Metabolism ◽  
Effector Molecule ◽  
Cytochrome Bd ◽  
Endogenous Production ◽  
Laboratory Culturing ◽  
H2s Production

H2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H2S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H2S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H2S, whereas H2S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H2S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H2S production, suggesting the involvement of multiple genes in H2S production. We identified endogenous H2S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H2S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H2S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.

scholarly journals Rapid Molecular Diagnosis of Tuberculosis and Its Resistance to Rifampicin and Isoniazid with Automated MDR/MTB ELITe MGB® Assay

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 797
Author(s):  
Vichita Ok ◽  
Alexandra Aubry ◽  
Florence Morel ◽  
Isabelle Bonnet ◽  
Jérôme Robert ◽  
...  
Keyword(s):  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Clinical Samples ◽  
Great Promise ◽  
Routine Practice ◽  
Pcr Assay ◽  
Perfect Agreement ◽  
Mdr Tb ◽  
Good Agreement

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.

scholarly journals Risk factors associated with multidrug-resistant tuberculosis in Espírito Santo, Brazil

2017 ◽  
Vol 51 (0) ◽  
Author(s):  
Geisa Fregona ◽  
Lorrayne Belique Cosme ◽  
Cláudia Maria Marques Moreira ◽  
José Luis Bussular ◽  
Valdério do Valle Dettoni ◽  
...  
Keyword(s):  
Previous Treatment ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Espírito Santo ◽  
Factors Associated ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
History Of ◽  
Espirito Santo

ABSTRACT OBJECTIVE To analyze the prevalence and factors associated with multidrug-resistant tuberculosis in Espírito Santo, Brazil. METHODS This is a cross-sectional study of cases of tuberculosis tested for first-line drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin) in Espírito Santo between 2002 and 2012. We have used laboratory data and registration of cases of tuberculosis – from the Sistema Nacional de Agravos de Notificação and Sistema para Tratamentos Especiais de Tuberculose. Individuals have been classified as resistant and non-resistant and compared in relation to the sociodemographic, clinical, and epidemiological variables. Some variables have been included in a logistic regression model to establish the factors associated with resistance. RESULTS In the study period, 1,669 individuals underwent anti-tuberculosis drug susceptibility testing. Of these individuals, 10.6% showed resistance to any anti-tuberculosis drug. The rate of multidrug resistance observed, that is, to rifampicin and isoniazid, has been 5%. After multiple analysis, we have identified as independent factors associated with resistant tuberculosis: history of previous treatment of tuberculosis [recurrence (OR = 7.72; 95%CI 4.24–14.05) and re-entry after abandonment (OR = 3.91; 95%CI 1.81–8.43)], smoking (OR = 3.93; 95%CI 1.98–7.79), and positive culture for Mycobacterium tuberculosis at the time of notification of the case (OR = 3.22; 95%CI 1.15–8.99). CONCLUSIONS The partnership between tuberculosis control programs and health teams working in the network of Primary Health Care needs to be strengthened. This would allow the identification and monitoring of individuals with a history of previous treatment of tuberculosis and smoking. Moreover, the expansion of the offer of the culture of tuberculosis and anti-tuberculosis drug susceptibility testing would provide greater diagnostic capacity for the resistant types in Espírito Santo.

scholarly journals First Evaluation of GenoType MTBDRplus2.0 Performed Directly on Respiratory Specimens in Central America

2016 ◽  
Vol 54 (10) ◽  
pp. 2498-2502 ◽  
Author(s):  
Fedora Lanzas ◽  
Thomas R. Ioerger ◽  
Harita Shah ◽  
William Acosta ◽  
Petros C. Karakousis
Keyword(s):  
Sensitivity And Specificity ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Content Type ◽  
Appropriate Treatment ◽  
Nitrate Reductase Assay ◽  
Frequent Mutations ◽  
Version 2.0 ◽  
Probe Assay ◽  
Respiratory Specimens

The turnaround times for conventional methods used to detectMycobacterium tuberculosisin sputum samples and to obtain drug susceptibility information are long in many developing countries, including Panama, leading to delays in appropriate treatment initiation and continued transmission in the community. We evaluated the performance of a molecular line probe assay, the Genotype MTBDRplusversion 2.0 assay, in detectingM. tuberculosiscomplex directly in respiratory specimens from smear-positive tuberculosis cases from four different regions in Panama, as well as the most frequent mutations in genes conferring resistance to isoniazid (katGandinhA) and rifampin (rpoB). Our results were confirmed with the nitrate reductase assay and genomic sequencing.M. tuberculosiscomplex was detected by the Genotype MTBDRplus2.0 assay with 100% sensitivity and specificity. The sensitivity and specificity for rifampin resistance were 100% and 100%, respectively, and those for isoniazid resistance were 90.7% and 100%. Isoniazid monoresistance was detected in 5.2% of new cases. Genotype MTBDRplus2.0 is highly accurate in detectingM. tuberculosiscomplex in respiratory specimens and is able to discriminate isoniazid-monoresistant cases from multidrug-resistant cases within 2 days.

scholarly journals Molecular evaluation of drug resistance in clinical isolates of Salmonella enterica serovar Typhi from Pakistan

2013 ◽  
Vol 7 (12) ◽  
pp. 929-940 ◽  
Author(s):  
Amna Afzal ◽  
Yasra Sarwar ◽  
Aamir Ali ◽  
Abbas Maqbool ◽  
Muhammad Salman ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Nalidixic Acid ◽  
Salmonella Enterica ◽  
Single Gene ◽  
Mutation Screening ◽  
Gene Cassette ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Fourth Generation ◽  
Salmonella Enterica Serovar Typhi

Introduction: This study aimed to determine the drug susceptibility patterns and genetic elements related to drug resistance in isolates of Salmonella enterica serovar Typhi (S. Typhi) from the Faisalabad region of Pakistan. Methodology: The drug resistance status of 80 isolates were evaluated by determining antimicrobial susceptibility, MICs, drug resistance genes involved, and the presence of integrons. Nalidixic acid resistance and reduced susceptibility to ciprofloxacin were also investigated by mutation screening of the gyrA, gyrB, parC, and parE genes. Results: Forty-seven (58.7%) isolates were multidrug resistant (MDR). Among the different resistance (R) types, the most commonly observed (13/80) was AmChStrTeSxtSmzTmp, which is the most frequent type observed in India and Pakistan. The most common drug resistant genes were blaTEM-1, cat, strA-strB, tetB, sul1, sul2, and dfrA7. Among the detected genes, only dfrA7 was found to be associated in the form of a single gene cassette within the class 1 integrons. Conclusions: MIC determination of currently used drugs revealed fourth-generation gatifloxacin as an effective drug against multidrug-resistant S. Typhi, but its clinical use is controversial. The Ser83→Phe substitution in gyrA was the predominant alteration in nalidixic acid-resistant isolates, exhibiting reduced susceptibility and increased MICs against ciprofloxacin. No mutations in gyrB, parC, or parE were detected in any isolate.

scholarly journals Association among biofilm formation, virulence gene expression, and antibiotic resistance in Proteus mirabilis isolates from diarrhetic animals in northeast China

2020 ◽  
Author(s):  
Yadong Sun ◽  
Shanshan Wen ◽  
Lili Zhao ◽  
Qiqi Xia ◽  
Yue Pan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antibiotic Resistance ◽  
Biofilm Formation ◽  
Northeast China ◽  
Virulence Gene ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Virulence Gene Expression ◽  
Biofilm Production ◽  
High Level

Abstract Background The aim of this study was to investigate the association among biofilm formation, virulence gene expression, and antibiotic resistance in P. mirabilis isolates collected from diarrhetic animals (n = 176) in northeast China between September 2014 and October 2016. Results Approximately 92.05% of the isolates were biofilm producers, whereas 7.95% of the isolates were non-producers. The prevalence of virulence genes in biofilm producers was significantly higher than that in non-producers. Biofilm production was significantly associated with the expression of ureC , zapA , rsmA , hmpA , mrpA , atfA , and pmfA ( P < 0.05). Drug susceptibility tests revealed that approximately 76.7% of the isolates were multidrug-resistant (MDR) and extensively drug-resistant (XDR). Biofilm production was significantly associated with resistance to doxycycline, tetracycline, sulfamethoxazole, kanamycin, and cephalothin ( P < 0.05). Although the pathogenicity of the biofilm producers was stronger than that of the non-producers, the biofilm-forming ability of the isolates was not significantly associated with morbidity and mortality in mice ( P > 0.05). Conclusion Our findings suggested that a high level of multidrug resistance in diarrhetic animals infected with P. mirabilis in northeast China.The results of this study indicated that the positive rates of the genes expressed by biofilm-producing P. mirabilis isolates were significantly higher than those expressed by non-producing isolates.

scholarly journals Cost of illness of non-multidrug-resistant tuberculosis in Germany: an update

2020 ◽  
Vol 6 (4) ◽  
pp. 00329-2020
Author(s):  
Roland Diel ◽  
Albert Nienhaus
Keyword(s):  
Central Committee ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Current Therapy ◽  
Productivity Losses ◽  
Public Health Screening ◽  
Mdr Tb ◽  
The Mean ◽  
Mean Cost

BackgroundA total of 5429 new cases of tuberculosis (TB) were reported in Germany in 2018; out of the 3780 TB cases for whom drug susceptibility testing was available, the proportion of multidrug-resistant TB (MDR-TB) cases was only 3.1% (118 cases).MethodsOn the basis of the current therapy guidelines of the German Central Committee against Tuberculosis, this study estimates the mean direct outpatient and combined in- and outpatient costs per non-MDR-TB patient from the perspective of the German statutory health insurance (SHI) system, together with costs arising from productivity losses and costs due to public health screening for TB in close contacts.ResultsFrom the insurance perspective, the mean outpatient costs (rounded) per case were €1628 for adults and €1179 for children for standard therapy; the mean cost of inpatient treatment amounted to €8626. The mean combined inpatient/outpatient cost was €8756 for adults and €8512 for children. As 95% of all TB patients were adults, the weighted treatment cost per patient in Germany in 2018 was €8746. These are in addition to the mean cost arising from productivity losses (€1839) and, weighted by pulmonary infectivity, cost of contact investigations (€368), coming to a total of €10 953.ConclusionGiven the clear increase in the number of non-MDR-TB cases since 2015, TB is still a disease of significant economic impact in Germany.

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