Multidrug-resistant Tuberculosis Research Articles

Predictors of poor treatment outcomes among drug-resistant tuberculosis patients in Hunan province, China

BackgroundDrug-resistant tuberculosis (DR-TB) is a significant public health concern, often resulting in poor treatment outcomes. This study aims to identify predictors of poor treatment outcomes among patients with DR-TB in Hunan Province, China. MethodsA retrospective cohort study was conducted in Hunan Province using data collected between 2013 and 2018 among patients with DR-TB treatment. Univariable and multivariable parametric survival analyses were performed using a shared frailty survival model with a Weibull distribution and Gamma frailty to identify determinants of poor treatment outcomes. Adjusted hazard ratios (AHR) with a 95 % confidence interval (CI) were calculated for the best-fitted model. The goodness of fit for the model was assessed using the Cox-Snell residual test. ResultsA total of 1384 bacteriologically confirmed DR-TB patients were included in the analysis. Of these, 9.97 % (95 % CI: 8.05–11.67 %) experienced poor treatment outcomes. The hazard of poor treatment outcomes was significantly higher among patients with a history of previous TB treatment compared to those with new TB (AHR = 1.82, 95 % CI: 1.27–2.61). Additionally, each one-day delay in diagnosis was associated with a slightly increased hazard of poor treatment outcomes (AHR = 1.00034, 95 % CI:1.000041–1.00064). Patients who received medication supervision and consistent treatment follow-up (i.e., systematic management) had a significantly lower hazard of poor treatment outcomes than those without systematic management (AHR = 0.08, 95 % CI: 0.05–0.14). ConclusionA substantial proportion of DR-TB patients in Hunan Province experience poor treatment outcomes, with prior TB treatment and delays in diagnosis being key predictors. Early diagnosis and systematic management, including medication supervision and consistent follow-up, significantly reduce the risk of poor treatment outcomes. Focused interventions for previously treated TB cases are crucial to improving treatment outcomes and mitigating the risk of long-term physical sequelae among DR-TB survivors.

A Unique Case of Pretonamid Resistance on MDR TB Patient: A Case Report

<i>Background</i>: Pretomanid is a novel medication that belongs to the class of nitroimid-azooxazines. The development of resistance to this novel agent not only complicates clinical management but also poses a threat to public health efforts aimed at controlling TB. This case report highlights the clinical presentation, laboratory findings, and therapeutic implications associated with a patient exhibiting pretonamid resistance. Through this examination, we aim to enhance understanding of resistance mechanisms, underscore the importance of ongoing surveillance, and advocate for refined treatment strategies in the context of MDR-TB management understanding the mechanism of this resistance is crucial for developing effective treatment strategy and improving patient outcome. <i>Case presentation</i>: a sixteen-year-old male patient diagnosed with rifampicin-resistant PTB (RR-PTB) after he presented with a cough of two weeks duration and he is on treatment for RR-PTB, and he is on BpaLM regimen. The third-month second-line phenotypic DST result revealed pretomanid (Pa) resistance. [Stm, INH, RIF, EMB, Pa are resistant, and Bdq, Clf, Dlm, Lfx, Lzd, and Mfx are sensitive]. <i>Clinical Discussion</i>: Following the hospital’s clinical panel team and national TB program expert’s discussion we changed the regimen to individualized (Lfx, Cs, Bdq, Dlm, Cfz and Lzd). <i>Conclusion</i>: Pretomanid resistance in humans reveals a low prevalence but highlight the need for vigilance. And since it’s the incorporated in BPaL regimine and its among the backbone of the regimen we should have to follow the resistance pattern. While facing Pretomanid resistance Consult experts, engage a physician experienced in drug-resistant TB for treatment planning and management, monitor adverse effects closely observe patients for signs of myelosuppression, peripheral neuropathy, and hepatotoxicity during treatment with the BPaL regimen. And also ensure timely susceptibility testing for all components of the BPaL regimen to guide effective treatment adjustments then go for alternative regimen.

Efficacy and Safety of Combined Bedaquiline and Delamanid Use among Patients with Multidrug-Resistant Tuberculosis in Beijing, China

ObjectivesThe combined use of bedaquiline and delamanid (BDQ-DLM) is limited by an increased risk of prolonging the QTc interval. We retrospectively evaluated patients who received DLM/BDQcontaining regimens at a TB-specialized hospital. We aimed to present clinical efficacy and safety data for Chinese patients. MethodsThis case–control study included patients with multidrug-resistant tuberculosis (MDR-TB) treated with BDQ alone or BDQ plus DLM. ResultsA total of 96 patients were included in this analysis: 64 in the BDQ group and 32 in the BDQ + DLM group. Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM, 46 patients (71.9%) in the BDQ group and 29 (90.6%) in the BDQ-DLM group achieved sputum culture conversion during treatment. The rate of sputum culture conversion did not differ between the two groups. The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group. The most frequent adverse event was QTc interval prolongation; however, the frequency of adverse events did not differ between the groups. ConclusionIn conclusion, our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB. Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Cytokines Levels and Anti-tuberculosis Drug Resistance among HIV Seropositive Patients in Ibadan, Southwest, Nigeria

Susceptibility to TB disease rises on mutations in cytokine receptors which ultimately lead to defective signaling and alter the immune surveillance and bacterial killing. Therefore, this study was undertaken to investigate the association between cytokines and anti-TB drug resistances. A total of 217 people living with human immunodeficiency virus at University College Hospital, Ibadan were recruited. Venous blood and sputum samples were collected. Sputum samples were cultured for Mycobacterium tuberculosis complex and characterized using standard methods. Anti-TB drug resistance was detected using phenotypic and genotypic methods. Cytokines levels (IL-10 and IFN-Y) were estimated using ELISA method. Association between cytokines and anti-TB drug resistance was determined using linear regression analysis. There were 105(48.4%) males and 112(51.6%) females with a mean age of 42.95 ± 8.286 years and a range of 28-65 years. The prevalence of TB among PLHIV was found to be 19.1% with male having higher rate than female (P<0.05), and highest rate among aged ≥40. There was no significant association between cytokines (IL-10 and IFN-y) and sex of the subjects (P>0.05). However, females had higher IFN-y level of 231.06±61.81 IU/ml when compared to 227.53±57.92 IU/ml obtained from males. The prevalence of multi-drug resistance TB was 11.9% with Rifampicin resistance having the highest rate of 5.5%. There was no significant association between cytokines (IL-10 and IFN-y) and sex, but age group >40 years had higher IL-10 and IFN-y level of 226.53±52.39 IU/ml and 232.41±66.63 IU/ml respectively. There was an association between high cytokines levels and anti-TB drug resistance (P<0.05). Highest cytokines levels; IL-10 (401.00±7.07 IU/ml) and IFN-Y (401.00±7.07 IU/ml) were recorded in Levofloxacin resistance. There was an association between high cytokines levels and genotypic anti- TB drug resistance (P<0.05) with highest cytokines levels; IL-10 (400.12±12.37 IU/ml) and IFN-Y (472.87±31.93 IU/ml) recorded in Rifampicin resistance. This entire study revealed that there is high prevalence of MDR-TB among PLHIV, with Rifampicin monoresistance having the highest resistance rate among the drugs tested, and pro and inflammatory cytokines (IL-10 and IFN-y) play significant role in the development of Multi Drug Resistant-Tuberculosis among people living with HIV.

Identification of Anti-Tuberculosis Drugs Targeting DNA Gyrase A and Serine/Threonine Protein Kinase PknB: A Machine Learning-Assisted Drug-Repurposing Approach

Tuberculosis (TB) is a global health challenge associated with considerable levels of illness and mortality worldwide. The development of innovative therapeutic strategies is crucial to combat the rise of drug-resistant TB strains. DNA Gyrase A (GyrA) and serine/threonine protein kinase (PknB) are promising targets for new TB medications. This study employed techniques such as similarity searches, molecular docking analyses, machine learning (ML)-driven absolute binding-free energy calculations, and molecular dynamics (MD) simulations to find potential drug candidates. By combining ligand- and structure-based methods with ML principles and MD simulations, a novel strategy was proposed for identifying small molecules. Drugs with structural similarities to existing TB therapies were assessed for their binding affinity to GyrA and PknB through various docking approaches and ML-based predictions. A detailed analysis identified six promising compounds for each target, such as DB00199, DB01220, DB06827, DB11753, DB14631, and DB14703 for GyrA; and DB00547, DB00615, DB06827, DB14644, DB11753, and DB14703 for PknB. Notably, DB11753 and DB14703 show significant potential for both targets. Furthermore, MD simulations’ statistical metrics confirm the drug–target complexes’ stability, with MM-GBSA analyses underscoring their strong binding affinity, indicating their promise for TB treatment even though they were not initially designed for this disease.

Repurposed Drugs and Plant-Derived Natural Products as Potential Host-Directed Therapeutic Candidates for Tuberculosis

Tuberculosis (TB) is one of the leading causes of death due to infectious disease. It is a treatable disease; however, conventional treatment requires a lengthy treatment regimen with severe side effects, resulting in poor compliance among TB patients. Intermittent drug use, the non-compliance of patients, and prescription errors, among other factors, have led to the emergence of multidrug-resistant TB, while the mismanagement of multidrug-resistant TB (MDR-TB) has eventually led to the development of extensively drug-resistant tuberculosis (XDR-TB). Thus, there is an urgent need for new drug development, but due to the enormous expenses and time required (up to 20 years) for new drug research and development, new therapeutic approaches to TB are required. Host-directed therapies (HDT) could be a most attractive strategy, as they target the host defense processes instead of the microbe and thereby may prevent the alarming rise of MDR- and XDR-TB. This paper reviews the progress in HDT for the treatment of TB using repurposed drugs which have been investigated in clinical trials (completed or ongoing) and plant-derived natural products that are in clinical or preclinical trial stages. Additionally, this review describes the existing challenges to the development and future research directions in the implementation of HDT.

Clonal Diversity and Spatial Dissemination of Drug-resistant Mycobacterium tuberculosis Complex among HIV Seropositive Patients in Southwest Nigeria

Mycobacterium tuberculosis complex display relatively static genomes and 99.9% nucleotide sequence identity. Studying the evolutionary history of such monomorphic bacteria is a difficult and challenging task. Therefore, this study was undertaken to investigate the clonal diversity and spatial dissemination of drug-resistant M. tuberculosis complex among HIV seropositive clients in Southwest Nigeria. A total of two-hundred and seventeen (217) consented HIV positive (case subjects) and fifty (50) non-HIV positive controls were recruited for this study. Two Sputum samples were collected from each participant in two consecutive days. The samples were divided into two parts: one part was decontaminated using NAOH-NALC method and aseptically cultured for Mycobacteria on Lowenstein-Jensen (LJ) medium with and without pyruvate. Mycobacterial isolates were characterized using conventional and molecular methods. Anti-TB drug sensitivity test was done using 1% proportion conventional method on LJ. MTBC isolates were sequenced using Genetic Analyzer 3130xl sequencer. Genetic relatedness and clonal diversity (phylogenetic analysis) of MTBC isolates were done using Bio- Edit software and MEGA 6. Out of 217 HIV positive participants, 105(48.4%) were male, while 112(51.6%) were female. Twenty-six (26(52.0%)) of the control subjects were male, while 24(48.0%) were females. The overall prevalence of TB among PLHIV was found to be 19.1%. The prevalence of NTM among PLHIV was found to be 2.8% with M. intracellulare being the predominant organism isolated. Participants’ age was found to be significantly associated with TB (P<0.05), however there was no significant association between TB and sex of the participants (P<0.05). The prevalence of culture confirmed drug-resistant TB (DR-TB) among PLHIV was found to be 11.9%, with Rifampicin having the highest monoresistance rate of 5.5%. The overall prevalence of MDR-TB among PLHIV was found to be 9.2%. The phylogenetic analysis of M. tuberculosis strains revealed same clone of all isolates. All PLHIV should be screened for drug-resistant TB especially MDR-TB as the prevalence of primary MDR-TB is high among them. Further study like 3R gene-based studies of adaptation and evolution is needed to facilitate further epidemiological studies of these bacteria.

Comorbidities and Treatment Outcomes in Patients Diagnosed with Drug-Resistant Tuberculosis in Rural Eastern Cape Province, South Africa.

Tuberculosis (TB) remains a significant global health challenge, with drug-resistant tuberculosis (DR-TB) posing a greater threat due to difficulty in treatment. This study aimed to investigate the relationship between comorbidities and treatment outcomes in patients diagnosed with DR-TB in rural Eastern Cape using logistic regression. Data on patient characteristics, comorbidities, and treatment outcomes were extracted from the medical records and analyzed using Python version 3.8. and R version 4.1.1 software. A logistic regression model was used to determine the effects of selected variables on treatment outcomes of DR-TB cases. Hearing loss and hypertension (HTN) were the most frequently observed comorbidities across various DR-TB cases, particularly rifampicin-resistant (RR), multidrug-resistant (MDR), and pre-extensively drug-resistant (pre-XDR-TB) cases. A hearing loss prevalence of 5.8% (26/445) was found among patients receiving treatment for TB, with the intensity of impairment ranging from mild to severe. Gender is significantly associated with the occurrence of HTN among these patients (p-value: 0.022). Comorbidities such as epilepsy, hearing loss, and HTN significantly impact treatment success, with higher risks of mortality and incomplete cure. Using logistic regression, obesity (OR = 3.0884; e = 1.1277; p = 0.0408) and HIV-positive status (OR = 0.4458; e = 0.8078; p = 0.0001) were highly likely and less likely associated with better treatment outcomes, respectively. The logistic regression model achieved an accuracy of 64.0%, a precision of 63.0%, and a recall of 95.0%, with an F-1 score of 76.0%. The findings underscore the importance of implementing integrated management strategies that address both DR-TB and its comorbidities, particularly in resource-limited settings where such patients are prevalent. Public health policies should incorporate strategies to provide nutritional assessments and interventions, particularly for individuals with low BMI. This could include food supplementation programs or partnerships with local food kitchens to ensure that patients have access to adequate nutrition during DR-TB treatment.

Electrochemical determination of clofazimine using a carbon dot polythionine nanocomposite modified screen‐printed electrode

Multi‐drug resistant Tuberculosis (MDR‐TB) treatment presents significant challenges for diagnosed patients, primarily due to the harsh side effects associated with treatment coupled with time‐consuming diagnostic techniques used to assess emergencies that arise from drug toxicity. Monitoring the antibiotics used in these treatments is vital to better understand the dosage requirements for affected patients. This study focuses on the fabrication, characterisation and sensor application of carbon dot polythionine (CDPTh) nanocomposites for the electrochemical detection of clofazimine (CFZ), a drug used in MDR‐TB treatment. CDPTh nanocomposites were electrochemically fabricated on a screen‐printed carbon electrode (SPCE) and

Introducing BPaL: Experiences from countries supported under the LIFT-TB project.

Previously, drug-resistant tuberculosis (DR-TB) patients were treated with long, toxic, and relatively ineffective regimens. However, in recent years, there have been major improvements made. The 2020 World Health Organization DR-TB Treatment guidelines recommended the use of a 6-months all-oral BPaL (bedaquiline, pretomanid and linezolid) regimen under operational research (OR) conditions for selected DR-TB patients. The processes, challenges, and interim results of introducing BPaL under OR conditions in 7 countries supported under the Korea International Cooperation Agency/TB Alliance-funded "Leveraging Innovation for Faster Treatment of Tuberculosis (LIFT-TB)" project are described here. The OR objectives were to explore the feasibility of introducing the BPaL regimen, and to estimate its effectiveness and safety in a select group of DR-TB patients. Between November 2020 and the end of March 2023, a total of 574 patients had been enrolled. Interim treatment success stands at an encouraging 90.9% (280/308). Although adverse events of special interest (AESI) were common, they were manageable, and only 1 patient had to discontinue the complete BPaL treatment regimen. In addition, no unexpected adverse events (AE) were seen. With careful advocacy, frequent communication with partners, and following steps to strengthen essential aspects of the delivery system, the project's experiences show that BPaL OR was feasible across different country settings. Project documents were constantly updated. The sharing of information, experiences, and interim results had a significant positive and motivating effect within and across countries. Interim OR results show excellent patient responses and are comparable to those seen under trial conditions. Although common, the observed AEs and AESIs were manageable, and no unexpected AEs were seen.

JIB-04, an inhibitor of Jumonji histone demethylase as a potent antitubercular agent against Mycobacterium tuberculosis.

The increasing drug resistance of Mycobacterium tuberculosis (Mtb), coupled with the limited availability of effective anti-tuberculosis medications, poses significant challenges for the management and treatment of tuberculosis (TB). Globally, non-tuberculous mycobacteria (NTM) infections are increasing, with Mycobacterium avium complex and Mycobacterium abscessus (Mab) being the most common in labs and having few treatment options. There's an urgent need for innovative therapies against Mtb and NTM that are effective and have minimal side effects. The study evaluated the in vitro efficacy of JIB-04, a Jumonji histone demethylase inhibitor, against Mtb, Mab, and multidrug-resistant (MDR) clinical isolates using the minimum inhibitory concentration (MIC) assay. We also determined the minimum bactericidal concentrations (MBCs) of JIB-04 against the H37Rv and H37Ra strains. A time-kill assay was performed to assess the comparative efficacy of JIB-04 and rifampicin against H37Ra. Additionally, the study investigated the impact of JIB-04 on biofilm formation and the persistence of H37Ra over extended periods. Our findings demonstrated a substantial inhibitory effect of JIB-04 on the growth of Mab, Mtb, and MDR clinical isolates. JIB-04 showed bactericidal effects at twice the MIC, outperforming rifampicin in reducing viable cell counts over 8 days. It showed moderate cytotoxicity to mammalian cells but effectively inhibited biofilm formation. In our anoxia model, JIB-04 induced a significant, concentration-dependent reduction in bacterial load. JIB-04 is a promising candidate for the treatment of MDR tuberculosis.

Trends of drug-resistant tuberculosis and risk factors to poor treatment-outcome: a database analysis in Littoral region-Cameroon, 2013-2022.

Tuberculosis(TB), currently has limited treatment options, and faces worldwide threat of drug-resistance(DR). In 2022, the DR-TB prevalence in Cameroon was 1.4% among new-cases and 8.3% among retreatment-cases. We analyzed the DR-TB database to descript the trends and DR-TB profile, treatment-outcome and associated risk-factors so-as-to propose measures to enhance program performance in Cameroon. We conducted a retrospective cohort study, analysed the DR-TB database of the Littoral region from 2013 to 2022. We appreciated the data-quality using zero-reporting, completeness, consistency, and validity indicators. We categorized DR-TB into Rifampicin-resistant-TB(RR-TB), multi-drug-resistant-TB(MDR-TB), pre-extensive-drug-resistant-TB(pre-XDR-TB), and XDR-TB and performed descriptive statistics. We assessed DR-TB treatment outcome targeting > 80% cure and/or completed treatment. Multiple logistic regression was used to determine risk factors related to poor treatment outcomes, and adjusted relative risk(RR) was considered significant at p < 0.05. Overall database quality was 93.7% with uniqueness 100%, data-completeness 82.5%, consistency 97% and validity 95.1%. A total of 567 DR-TB cases were reported, with median age of 34 (1-80) years, male-to-female sex ratio (3:2). Cases were classified as 19(3.4%) RR-TB, 536(94.6%) MDR-TB, 7(1.3%) pre-XDR-TB, and 4(0.7%) XDR-TB. Case-reporting increased from 2013, reaching their peak in 2018. The overall treatment refusal rate was 123(11.9%) and treatment outcomes of 270(60.8%) cured, 116(26.4%) completed, 32(7.2%) deaths, 19(4.3%) lost-to-follow-up, and 6(1.4%) failure were recorded. We identified 84 dead (CFR:14.8%) amongst whom 52(62%) refused treatment, 17(20%) occurred during the first month of therapy and 13(15.5%) HIV-TB co-infected. Male gender [p = 0.006, RR = 2.5 (95% CI: 1.3-4.7)], HIV positive status [p = 0.012, RR = 2.1 (95% CI: 1.2-3.7)], and previous DR-TB status [p = 0.02, RR = 3.9 (95% CI: 1.3-12.0)] were statistically associated to poor treatment outcomes. In the Littoral Region-Cameroon, cases of DR-TB increased from 2013, reaching their peak in 2018 befor dropping right up to 2022. RR-TB, MDR-TB, Pre-XDR-TB and XDR-TB represented 3.4%, 94.6%, 1.3% and 0.7% of all reported DR-TB cases. Overall, DR-TB treatment success rate was 87.2%. Male-gender, HIV-positive status, and previous DR-TB are associated with poor TB treatment outcomes. We recommend universal drug susceptibility testing to ensure early/maximum DR-TB case-detection and proper pre-treatment counselling to limit the high death rates and anti-TB treatment refusal rates which are setbacks from achieving end-TB strategies.

Circulation of &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; strains of the Beijing Central Asian Outbreak genotype in the Kemerovo region — Kuzbass in 2018–2022

Introduction. The Kemerovo region — Kuzbass is characterized by a high prevalence of multidrug-resistant (MDR) tuberculosis (TB), including coinfection with HIV (HIV/TB). A previously unknown in Russia relationship between MDR and the Beijing Central Asian Outbreak (CAO) subtype has been discovered, which updates studies of Mycobacterium tuberculosis taking into account this resistant variant. Objective: to study the molecular genetic structure of the M. tuberculosis population, to assess the prevalence and possible routes of emergence of Beijing CAO strains in the Kemerovo region — Kuzbass. Materials and methods. A total of 325 M. tuberculosis strains were studied in 2018–2022 using spoligotyping, MIRU-VNTR 24 and SNP typing. Whole genome sequencing and bioinformatics analysis were performed for seven Beijing CAO strains. Results. Primary MDR and pre-extensive drug resistance (pre-XDR) were detected in 39.4% and 11.5% of strains, respectively. In the total sample, MDR was 43.4%, pre-XDR — 19.7%. In the structure of the M. tuberculosis population, the Beijing genotype prevailed (78.8%), with its subtypes Central Asian Russian (40.9%) and B0/W148 (32.6%). The Euro-American lineage (27.3%) was represented by the genotypes T (6.5%), LAM (5.8%), Ural (4.9%), H (0.9%); one strain CAS1-Delhi was detected, the genotype of 2.8% of strains was not identified. The proportion of Beijing CAO was 12.6% of the total sample; this subtype was significantly more often detected among HIV/TB (20.6%) than in HIV-negative TB patients (9.1%; p = 0.005). The results of the Beijing CAO genome analysis from the Kemerovo region indicate the absence of a direct chain of transmission between these TB cases. A hypothesis has been put forward about the introduction of Beijing CAO to the Kemerovo region from Central Asia and its endemic circulation in the region. Conclusion. A high level of MDR and pre-XDR was detected in Beijing genotype strains in the M. tuberculosis population of the Kemerovo region — Kuzbass, especially the B0/W148 (97.2%) and CAO (87.5%) subtypes. Beijing CAO strains, detected mainly in newly diagnosed HIV/TB patients, require further monitoring and control of their spreading.

Evaluation of Treatment Outcome Among MDR-TB Patients in Respect to Their Diabetic Status

Diabetes mellitus is an established risk factor of tuberculosis. Failure of the tubercular treatment outcome is higher among patients who are simultaneously suffering from diabetes. This study aims to observe the treatment outcome of the multi drug resistant tuberculosis patients in respect to their diabetic status. This cross sectional study has been conducted in a tertiary level hospital specialized for the diseases of the chest, during the period of January to December of the year 2019. Ethical approval for the research work has been acquired and informed written consent from the patients has been taken prior conducting the study and data collection. Face to face interview and review of medical records has been undertaken to collect data. Collected data has been analyzed with IBM SPSS software. Among 200 respondents, 53.0% patients showed to have early treatment response whereas, 47.0% had delayed treatment response. Among them, 80 patients were diabetic, where, 82.5.0% showed to have delayed response to the treatment and only 17.5% had early response to the treatment. Out of 120 non-diabetic respondents 77.5% had early response to the treatment and 22.5% had delayed response to the treatment. The treatment outcome of an MDR-TB patient found to be dependent on patient’s gender, age, marital status, monthly family income, history of previous TB treatment and also diabetic status (p&lt;0.05). According to this study, diabetic MDR-TB patients are on increased risk of responding late to the treatments than the non-diabetic MDR-TB patients.

Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling.

Mycobacteria are opportunistic intracellular pathogens that have plagued humans and other animals throughout history and still are today. They manipulate and hijack phagocytic cells of immune systems, enabling them to occupy this peculiar infection niche. Mycobacteria exploit a plethora of mechanisms to resist antimicrobials (e. g., waxy cell walls, efflux pumps, target modification, biofilms, etc.) thereby evolving into superbugs, such as extensively drug-resistant tuberculosis (XDR TB) bacilli and the emerging pathogenic Mycobacterium abscessus complex. This review summarizes the mechanisms of action of some of the surging antimycobacterial strategies. Exploiting the fact that mycobacteria are obligate aerobes and the differences between their oxidative phosphorylation pathways versus their human counterpart opens a promising avenue for drug discovery. The polymorphism of respiratory complexes across mycobacterial pathogens imposes challenges on the repositioning of antimycobacterial agents to battle the rise in nontuberculous mycobacterial infections. In silico strategies exploiting mycobacterial respiratory machinery data to design novel therapeutic agents are touched upon. The potential druggability of mycobacterial respiratory elements is reviewed. Future research addressing the health challenges associated with mycobacterial pathogens is discussed.

Risk Factors for the Incidence of Drug-Resistant Tuberculosis in the Labuang Baji Hospital: A Healthpreneur Perspective

Risk Factors for the Incidence of Drug-Resistant Tuberculosis in the Labuang Baji Hospital: A Healthpreneur Perspective

Integrated virtual screening and MD simulation study to discover potential inhibitors of mycobacterial electron transfer flavoprotein oxidoreductase.

Tuberculosis (TB) continues to be a major global health burden, with high incidence and mortality rates, compounded by the emergence and spread of drug-resistant strains. The limitations of current TB medications and the urgent need for new drugs targeting drug-resistant strains, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, underscore the pressing demand for innovative anti-TB drugs that can shorten treatment duration. This has led to a focus on targeting energy metabolism of Mycobacterium tuberculosis (Mtb) as a promising approach for drug discovery. This study focused on repurposing drugs against the crucial mycobacterial protein, electron transfer flavoprotein oxidoreductase (EtfD), integral to utilizing fatty acids and cholesterol as a carbon source during infection. The research adopted an integrative approach, starting with virtual screening of approved drugs from the ZINC20 database against EtfD, followed by molecular docking, and concluding with molecular dynamics (MD) simulations. Diacerein, levonadifloxacin, and gatifloxacin were identified as promising candidates for repurposing against TB based on their strong binding affinity, stability, and interactions with EtfD. ADMET analysis and anti-TB sensitivity predictions assessed their pharmacokinetic and therapeutic potential. Diacerein and levonadifloxacin, previously unexplored in anti-tuberculous therapy, along with gatifloxacin, known for its efficacy in drug-resistant TB, have broad-spectrum antimicrobial properties and favorable pharmacokinetic profiles, suggesting potential as alternatives to current TB treatments, especially against resistant strains. This study underscores the efficacy of computational drug repurposing, highlighting bacterial energy metabolism and lipid catabolism as fruitful targets. Further research is necessary to validate the clinical suitability and efficacy of diacerein, levonadifloxacin, and gatifloxacin, potentially enhancing the arsenal against global TB.

Time to Cure and Predictive Factors Among Patients with Multi-Drug Resistance Tuberculosis in Puntland, Somalia: A Retrospective Cohort Study

Background: Multi-drug-resistant tuberculosis, also known as MDR-TB, is caused by bacteria that are resistant to the most effective first-line anti-tuberculosis medications, which are rifampicin and isoniazid. MDR-TB is an increasing global concern, and its spread has varying cure times for patients affected. Thus, this study was intended to investigate the median time to cure and identify predictive factors for patients with MDR-TB in Puntland, Somalia. Methods: A retrospective cohort study was carried out at the MDR-TB center in Galkayo, Puntland, Somalia between the years of July 2017 and August 2023. The study utilized data that were collected from the inquiry form and monitoring cards of a randomly selected sample of 130 patients over a 6-year period. The data were entered into Epi-Data version 4.3 and analyzed using R Programming version 4.4.0. Non-parametric methods were used to estimate the median time to cure for patients with MDR-TB. Semi-parametric and parametric models were employed to determine predictive factors that influence the time to cure for MDR-TB patients. The Akaike Information Criteria (AIC) and Bayesian Information Criteria (BIC) of different survival models were compared to select the model that offers the best fit. Results: Out of the total of MDR-TB patients, 109(83.85%) were cured and 21(16.15%) were censored during the follow-up period. The median time to cure from MDR-TB was found to be 619 days which is approximately 20 months. In accordance with the AIC and BIC, the Log-logistic accelerated failure time model was the best fit for the data as compared to the other AFT models. The result of the Log-logistic AFT model revealed that age, sex, disease site, and comorbidities significantly affect the time to cure for MDR-TB. According to this study, older age with MDR-TB patients, male MDR-TB patients, MDR-TB patients with comorbid conditions, and extrapulmonary MDR-TB patients had a longer time to cure than their reference categories. Conclusion: Based on the findings of the study, the median time to cure for patients with MDR-TB in Puntland was found to be 20 months. Sex, disease site, comorbidities and age were predictive factors of time to cure from MDR-TB.

Small Molecule Inhibitors of Mycobacterium tuberculosis Topoisomerase I Identified by Machine Learning and In Vitro Assays.

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a leading infectious cause of death globally. The treatment of patients becomes much more difficult for the increasingly common multi-drug resistant TB. Topoisomerase I is essential for the viability of M. tuberculosis and has been validated as a new target for the discovery of novel treatment against TB resistant to the currently available drugs. Virtual high-throughput screening based on machine learning was used in this study to identify small molecules that target the binding site of divalent ion near the catalytic tyrosine of M. tuberculosis topoisomerase I. From the virtual screening of more than 2 million commercially available compounds, 96 compounds were selected for testing in topoisomerase I relaxation activity assay. The top hit that has IC50 of 7 µM was further investigated. Commercially available analogs of the top hit were purchased and tested with the in vitro enzyme assay to gain further insights into the molecular scaffold required for topoisomerase inhibition. Results from this project demonstrated that novel small molecule inhibitors of bacterial topoisomerase I can be identified starting with the machine-learning-based virtual screening approach.

Assessing the Impact of Bedaquiline, Clofazimine, and Linezolid on Mycobacterial Genome Integrity.

Tuberculosis (TB) presents significant medical challenges, largely due to the genetic diversity of Mycobacterium tuberculosis, which enhances the resilience and resistance of the pathogen to first-line treatments. In response to the global rise of drug-resistant TB, second-line antitubercular drugs like bedaquiline (BDQ), linezolid (LZD), and clofazimine (CFZ) have become critical treatment options. Understanding the molecular changes these drugs induce is essential for optimizing TB therapy. To contribute to this effort, we investigated their impact on genome maintenance and stability using Mycobacterium smegmatis as a model organism. Using mutation accumulation assays and whole-genome sequencing, we found that the second-line antibiotics did not significantly increase mutation rates, unlike the positive control UV treatment. However, upon BDQ treatment, we detected mutations in transporter proteins and transcription factors without any increase in the minimal inhibitory concentration. Additionally, BDQ and CFZ were found to alter DNA repair pathways and reduce cellular dNTP levels, particularly CFZ, which depleted dGTP, impacting DNA synthesis. CFZ also upregulated DNA repair enzymes, enhancing error-free repairs. Despite minimal mutagenic effects, both drugs displayed distinct impacts on cellular mechanisms, suggesting additional modes of action.