Tuberculosis Treatment Regimens Research Articles

Molecular insights into Mmpl3 leads to the development of novel indole-2-carboxamides as antitubercular agents.

Tuberculosis (TB) is an air-borne infectious disease and is the leading cause of death among all infectious diseases globally. The current treatment regimen for TB is overtly long and patient non-compliance often leads to drug resistant TB resulting in a need to develop new drugs that will act via novel mechanisms. In this research work, we selected Mycobacterium membrane protein large (MmpL3) as the drug target and indole-2-carboximide as our molecule of interest for further designing new molecules. A homology model was prepared for the Mycobacterium tuberculosis MmpL3 from the crystal structure of Mycobacterium smegmatis MmpL3. A series of indoles which are known to be MmpL3 inhibitors were docked in the prepared protein and the binding site properties were identified. Based on that, 10 molecules were designed and synthesized and their antitubercular activities evaluated. We identified four hits among which the highest potency candidate possessed a minimum inhibitory concentration (MIC) of 1.56 μM at 2-weeks. Finally, molecular dynamics simulation studies were done with 3b and a previously reported MmpL3 inhibitor to understand the intricacies of their binding in real time and to correlate the experimental findings with the simulation data.

ANALYSIS OF THE EFFECTIVENESS OF DIFFERENT TREATMENT REGIMENS FOR DRUG-RESISTANT TUBERCULOSIS IN PRYKARPATTIA. CHALLENGES OF OUR TIME

The aim: To study the structure of adverse drug reactions and the effectiveness of treatment among patients with drug-resistant tuberculosis who follow the modified short-term and individualized treatment regimens. Materials and methods: The analysis of 138 inpatient medical records, outpatient health cards and electronic database of the patient register was conducted. Resistant strains of MTB were microbiologically verified in all the patients. All the patients underwent clinical-laboratory, instrumental microbiological, genetic-molecular (GeneXpert MTB / RIF) methods of examination, both for diagnosis and monitoring of the effectiveness of treatment. In order to prevent complications and control adverse reactions, all the patients were briefly screened for peripheral neuropathy, basic audiometry, the QTc interval was determined, visual acuity and color perception were checked. Results: At individualized treatment regimen of tuberculosis, adverse reactions were 3.5 times more common than in patients with modified short-term therapy, in 65 (68.4%) cases and in 8 (18.6%) cases, respectively. Accordingly, the effectiveness of treatment differed in both groups. Prevailing in long-term treatment were: treatment interruption treatment gap, treatment failure, continued treatment. In patients receiving short-term regimens, the cured rate was almost twice as common as in the second group. Conclusions: Timely detection cases of resistant tuberculosis and using linear probe analysis (LPA) - GenoType MTBDRplus for diagnosis of fluoroquinolone resistance, will allow the use of modified short-term treatment regimens for tuberculosis. Which in turn will reduce the number of side effects and improve the outcome of treatment.

Prevalence and Determinants of Type 2 Diabetes among the Pulmonary Tuberculosis Cases in Nepal: A Cross Sectional Study

Background Since prehistoric time to the earlier 20th century, diabetes was accounted as comorbidity among tuberculosis patients, which is reducing the treatment efficiency.
 Objective To investigate the prevalence and determinants of type 2 diabetes mellitus among tuberculosis patients in central development region of Nepal.
 Method An analytical cross-sectional study was conducted by using structured questionnaire. Face to face interview as well as reviewing of the medical records of the tuberculosis cases has been performed during September 2018 - February 2019. The systematic random sampling was applied to select 306 tuberculosis cases. Then the respondents were examined for blood glucose level as well as Glycated haemoglobin (HbA1c) level to identify TB with Diabetes Mellitus. The proportion of respondents with fasting blood glucose level ≥ 126 mg/dl or a random blood glucose ≥ 200 mg/dl was considered as Tuberculosis with Diabetes Mellitus cases. Similarly, haemoglobin A1C ≥ 7% was accessed as amplified risk for tuberculosis. Multiple logistic regression was performed to analyse the factors associated with Tuberculosis with Diabetes Mellitus by using STATA. P value < 0.05 was taken as statistically significant.
 Result A total of 306 tuberculosis patients were included in the study. The mean ± standard deviation of age of participants was 36.82±15.94 years. The proportion of male slightly exceeded than that of female with a ratio of 1.73:1. The prevalence of TBDM was 17.32% (95% CI: 13.05-21.58) of all diagnosed tuberculosis cases. Our multivariable analysis identified the factors those were associated with TBDM were age ≥ 45 years (adj.OR=3.97, 95% CI 1.81-8.71, p value 0.001), patients residing in the urban areas (adj.OR=9.75, 95% CI 1.99-47.6, p value 0.005), had Body Mass Index (BMI) <18.5 Kg/m2 (adj.OR=3.20, 95% CI 1.58-6.51, p value 0.001), had diastolic blood pressure ≥ 80 mmHg (adj.OR=2.34, 95% CI 1.17-4.66, p value 0.015) and patients who were treated with Cat II and Cat III tuberculosis treatment regimens (adj.OR=2.65, 95% CI 1.22-5.73, p value 0.013).
 Conclusion The prevalence of type 2 diabetes mellitus among tuberculosis patients was higher than prevalence of diabetes in general population of Nepal and it was higher among male, urban residents, patients with low BMI and the older aged tuberculosis patients.

Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production

Ergothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.

Comparative Performance of Genomic Methods for the Detection of Pyrazinamide Resistance and Heteroresistance in Mycobacterium tuberculosis.

ABSTRACTPyrazinamide is an important component of both drug-susceptible and drug-resistant tuberculosis treatment regimens. Although approximately 50% of rifampin-resistant isolates are also resistant to pyrazinamide, pyrazinamide susceptibility testing is not routinely performed due to the challenging nature of the assay. We investigated the diagnostic accuracy of genotypic and phenotypic methods and explored the occurrence of pyrazinamide heteroresistance. We assessed pyrazinamide susceptibility among 358 individuals enrolled in the South African EXIT-RIF cohort using Sanger and targeted deep sequencing (TDS) of the pncA gene, whole-genome sequencing (WGS), and phenotypic drug susceptibility testing. We calculated the diagnostic accuracy of the different methods and investigated the prevalence and clinical impact of pncA heteroresistance. True pyrazinamide susceptibility status was assigned to each isolate using the Köser classification and expert rules. We observed 100% agreement across genotypic methods for detection of pncA fixed mutations; only TDS confidently identified three isolates (0.8%) with minor variants. For the 355 (99.2%) isolates that could be assigned true pyrazinamide status with confidence, phenotypic DST had a sensitivity of 96.5% (95% confidence interval [CI], 93.8 to 99.3%) and specificity of 100% (95% CI, 100 to 100%), both Sanger sequencing and WGS had a sensitivity of 97.1% (95% CI, 94.6 to 99.6%) and specificity of 97.8% (95% CI, 95.7 to 99.9%), and TDS had sensitivity of 98.8% (95% CI, 97.2 to 100%) and specificity of 97.8% (95% CI, 95.7 to 99.9%). We demonstrate high sensitivity and specificity for pyrazinamide susceptibility testing among all assessed genotypic methods. The prevalence of pyrazinamide heteroresistance in Mycobacterium tuberculosis isolates was lower than that identified for other first-line drugs.

Wastewater-Based Surveillance of Antibiotic Resistance Genes Associated with Tuberculosis Treatment Regimen in KwaZulu Natal, South Africa.

Essential components of public health include strengthening the surveillance of infectious diseases and developing early detection and prevention policies. This is particularly important for drug-resistant tuberculosis (DR-TB), which can be explored by using wastewater-based surveillance. This study aimed to use molecular techniques to determine the occurrence and concentration of antibiotic-resistance genes (ARGs) associated with tuberculosis (TB) resistance in untreated and treated wastewater. Raw/untreated and treated (post-chlorination) wastewater samples were taken from three wastewater treatment plants (WWTPs) in South Africa. The ARGs were selected to target drugs used for first- and second-line TB treatment. Both conventional polymerase chain reaction (PCR) and the more advanced droplet digital PCR (ddPCR) were evaluated as surveillance strategies to determine the distribution and concentration of the selected ARGs. The most abundant ARG in the untreated wastewater was the rrs gene, associated with resistance to the aminoglycosides, specifically streptomycin, with median concentration ranges of 4.69–5.19 log copies/mL. In contrast, pncA gene, associated with resistance to the TB drug pyrazinamide, was the least detected (1.59 to 2.27 log copies/mL). Resistance genes associated with bedaquiline was detected, which is a significant finding because this is a new drug introduced in South Africa for the treatment of multi-drug resistant TB. This study, therefore, establishes the potential of molecular surveillance of wastewater for monitoring antibiotic resistance to TB treatment in communities.

Genomic Profiling of Mycobacterium tuberculosis Strains, Myanmar.

Multidrug resistance is a major threat to global elimination of tuberculosis (TB). We performed phenotypic drug-susceptibility testing and whole-genome sequencing for 309 isolates from 342 consecutive patients who were given a diagnosis of TB in Yangon, Myanmar, during July 2016‒June 2018. We identified isolates by using the GeneXpert platform to evaluate drug-resistance profiles. A total of 191 (62%) of 309 isolates had rifampin resistance; 168 (88%) of these rifampin-resistant isolates were not genomically related, indicating the repeated emergence of resistance in the population, rather than extensive local transmission. We did not detect resistance mutations to new oral drugs, including bedaquiline and pretomanid. The current GeneXpert MTB/RIF system needs to be modified by using the newly launched Xpert MTB/XDR cartridge or line-probe assay. Introducing new oral drugs to replace those currently used in treatment regimens for multidrug-resistant TB will also be useful for treating TB in Myanmar.

On the Mechanism of Development of Autoimmune Diseases Following Exposure to Inactivated Mycobacterium tuberculosis

factors, and inadequate hygiene practices contribute to high incidence of tuberculosis in the world. Effective disease prevention shall be based on scientific substantiation of causality and the mechanisms of its development. Objective: The study aimed to investigate the etiopathogenesis of autoimmune disorders associated with the exposure of warm-blooded animals to heat killed M. tuberculosis. Materials and methods: We determined hematological parameters of old Wistar rats using standard methods and estimated the activity of lactate and succinate dehydrogenases (LDH, SDH) in lymphocytes (mitochondria) using a cytobiochemical method. The clinical and laboratory results were confirmed by X-ray tests. Results: Inflammation induced by administration of heat inactivated M. tuberculosis (complete Freund’s adjuvant (CFA)) reached the maximum during the third week: the number of white blood cells increased from (9.8 to 11.3) × 109/L compared to the control animals, normalizing by the seventh week. By the end of the first week, there was a pronounced immune response manifested by the increased erythrocyte sedimentation rate, which later exceeded the threshold limit by 87–100 %. The autoimmune disease progression was accompanied by impaired cellular respiration (glycolysis and oxidative phosphorylation) by 40 % and 77 %, respectively (p < 0.01). X-ray revealed disorders in the articular apparatus of the exposed animals including signs of rheumatoid arthritis and bone resorption. Conclusion: The mechanism of immunotoxicity of M. tuberculosis is associated with impaired energy supply of immune cells and changes in their morpho-functional properties. Based on our findings, we recommend inclusion of drugs with immunomodulatory, antihypoxic and osteoprotective mechanisms in treatment and prevention regimens for tuberculosis and associated diseases to enhance therapeutic efficacy.

Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening.

Decaprenylphosphoryl-β-D-ribose oxidase (DprE1) plays important roles in the biosynthesis of mycobacterium cell wall. DprE1 inhibitors have shown great potentials in the development of new regimens for tuberculosis (TB) treatment. In this study, an integrated molecular modeling strategy, which combined computational bioactivity fingerprints and structure-based virtual screening, was employed to identify potential DprE1 inhibitors. Two lead compounds (B2 and H3) that could inhibit DprE1 and thus kill Mycobacterium smegmatis in vitro were identified. Moreover, compound H3 showed potent inhibitory activity against Mycobacterium tuberculosis in vitro (MICMtb = 1.25 μM) and low cytotoxicity against mouse embryo fibroblast NIH-3T3 cells. Our research provided an effective strategy to discover novel anti-TB lead compounds.

Diagnostic Accuracy of Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis: A Systematic Review with Meta-Analysis.

Introduction: Pyrazinamide (PZA) susceptibility testing plays a critical role in determining the appropriate treatment regimens for multidrug-resistant tuberculosis. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of sequencing PZA susceptibility tests against culture-based susceptibility testing methods as the reference standard. Methods: We searched the MEDLINE/PubMed, Embase, and Web of Science databases for the relevant records. The QUADAS-2 tool was used to assess the quality of the studies. Diagnostic accuracy measures (i.e., sensitivity and specificity) were pooled with a random-effects model. All statistical analyses were performed with Meta-DiSc (version 1.4, Cochrane Colloquium, Barcelona, Spain), STATA (version 14, Stata Corporation, College Station, TX), and RevMan (version 5.3, The Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark) software. Results: A total of 72 articles, published between 2000 and 2019, comprising data for 8,701 isolates of Mycobacterium tuberculosis were included in the final analysis. The pooled sensitivity and specificity of the PZA sequencing test against all reference tests (the combination of BACTEC mycobacteria growth indicator tube 960 (MGIT 960), BACTEC 460, and proportion method) were 87% (95% CI: 85-88) and 94.7% (95% CI: 94-95). The positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the curve estimates were found to be 12.0 (95% CI: 9.0-16.0), 0.17 (95% CI: 0.13-0.21), 106 (95% CI: 71-158), and 96%, respectively. Deek's test result indicated a low likelihood for publication bias (p = 0.01). Conclusions: Our analysis indicated that PZA sequencing may be used in combination with conventional tests due to the advantage of the time to result and in scenarios where culture tests are not feasible. Further work to improve molecular tests would benefit from the availability of standardized reference standards and improvements to the methodology.

Early phase of effective treatment induces distinct transcriptional changes in Mycobacterium tuberculosis expelled by pulmonary tuberculosis patients

Effective treatment reduces a tuberculosis patient's ability to infect others even before they test negative in sputum or culture. Currently, the basis of reduced infectiousness of the Mycobacterium tuberculosis (Mtb) with effective treatment is unclear. We evaluated changes in aerosolized bacteria expelled by patients through a transcriptomic approach before and after treatment initiation (up to 14 days) by RNA sequencing. A distinct change in the overall transcriptional profile was seen post-treatment initiation compared to pretreatment, only when patients received effective treatment. This also led to the downregulation of genes associated with cellular activities, cell wall assembly, virulence factors indicating loss of pathogenicity, and a diminished ability to infect and survive in new host cells. Based on this, we identified genes whose expression levels changed with effective treatment. The observations of the study open up avenues for further evaluating the changes in bacterial gene expression during the early phase of treatment as biomarkers for monitoring response to tuberculosis treatment regimens and provide means of identifying better correlates of Mtb transmission.

Active surveillance for adverse events in patients on longer treatment regimens for multidrug-resistant tuberculosis in Viet Nam.

ObjectiveManagement of multidrug-resistant tuberculosis (MDR-TB) is a significant challenge to the global healthcare system due to the complexity and long duration of the MDR-TB treatment. This study analyzed the safety of patients on longer injectable-based MDR-TB treatment regimens using active pharmacovigilance data.MethodWe conducted an observational, prospective study based on active pharmacovigilance within the national TB program. A total of 659 MDR-TB patients were enrolled and followed up at 9 TB- hospitals in 9 provinces of all 3 regions in Vietnam between 2014 and 2016. Patients received a treatment regimen (standardized or individualized) based on their drug susceptibility test result and their treatment history. Baseline and follow-up information was collected at the start and during treatment. Adverse events (AE) were defined and classified as serious adverse events (SAEs) or otherwise. Multivariate Cox regression following the Iterative Bayesian Model Averaging algorithm was performed to identify factors associated with AE occurrence.ResultsOut of 659 patients assessed, 71.3% experienced at least one AE, and 17.5% suffered at least one SAE. The most common AEs were gastrointestinal disorders (38.5%), arthralgia (34.7%), and psychiatric disorders (30.0%). The proportion of patients with nephrotoxicity and hearing loss or vestibular disorders were 7.4% and 15.2%, respectively. 13.1% of patients required modifications or interruption of one or more drugs. In 77.7% of patients, treatment was completed successfully, while 9.3% lost to follow-up, in 3.0% treatment failed, and 7.4% died. Some significant risk factors for nephrotoxicity included diabetes mellitus (HR = 8.46 [1.91–37.42]), renal dysfunction (HR = 8.46 [1.91–37.42]), alcoholism (HR = 13.28 [5.04–34.99]), and a higher average daily dose of injectable drugs (HR = 1.28 [1.14–1.43]).ConclusionWhile a majority of patients on the longer injectable-based regimens experienced non-serious AEs during MDR-TB treatment, one in six patients experienced at least an SAE. Active TB drug-safety monitoring is useful to understand the safety of MDR-TB treatment and explore the risk factors for toxicity. All-oral, shorter MDR-TB regimens might be able to reduce the inconvenience, discomfort, and toxicity of such regimens and increase adherence and likelihood of successful completion.

Pretomanid: Clinical Trials and Prospects to Be Used in Treatment Regimens for Multiple and Extensive Drug Resistant Tuberculosis

The article presents the review of 68 publications, recommendations, and guidelines on clinical trials of pretomanid for the treatment of patients with drug resistant tuberculosis. According to the publications, combinations of pretomanid with other anti-tuberculosis drugs are highly effective and promising in the treatment of such patients.

Late Discovering Spina Ventosa: A Case Report

IntroductionSpina Ventosa is a rare condition that is easy to misdiagnose as other diseases. We present a case of late-diagnosed Spina Ventosa, which had not only the osteoarticular tuberculosis symptoms but also some severe symptoms, including pleural effusion, ascites, and anemia. By intensive treatment, our patient recovered completely.Case ReportA 7-year-old boy was admitted with complaints of painless swelling of metacarpals, metatarsals, and phalanges of his hands and feet and a discharging sinus of the left toe. There was no family or past history of tuberculosis. His immunizations were up to date. General examination revealed that the child had pallor and was emaciated. No lymphadenopathy was detected. Investigations revealed hemoglobin: 74 g/l, and erythrocyte sedimentation rate (ESR) was 42 mm/hour. QuantiFERON-TB test was positive. The radiograph showed irregular swelling with sclerosis of the underlying bones. The right-hand x-ray showed cortical destruction, sclerosis, and cystic expansion or right second metacarpal. Chest x-ray indicated pleural effusion. Histopathological examination of specimen from the foot and lung and abdomen fluid confirmed tuberculosis. The child was treated with the first-line tuberculosis treatment regimen (Isoniazid, Rifampicin, Ethambutol, and Pyrazinamide) for two months, followed by Isoniazid, Rifampicin, and Pyrazinamide for a further four months. His lesions disappeared after six weeks of intensive treatment.ConclusionA delay in diagnosis and treatment of tuberculosis can lead to systemic manifestations in multiple organs. Despite the delay in diagnosis, this child had a good outcome due to being treated promptly and adequately after the presentation.

Mycobacterium Tuberculosis infection in Patients with Hematologic Malignancies in an Endemic Setting: An Initial Analysis

Introduction: Patients with hematologic malignancies (HM) are at high risk for developing concomitant infections given their immunosuppression. Tuberculosis (TB) is a worldwide public health issue which affects developing countries most severely, and within them, patients with decreased immunity are most vulnerable. There are few studies examining the clinical factors associated with development of TB and survival, this is especially true in high-endemic developing countries where previous analysis have considered both microbiologically confirmed and suspected TB.Objective: Our primary objective was to examining clinical and pathologic factors associated with development of clinically active TB in a cohort of patients with HM and microbiologically confirmed TB. A secondary objective was to analyze factors associated with survivalMethods: This single-center retrospective cohort study included 46 adult patients with HM (Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia) and subsequent development of clinically active TB with microbiological confirmation (either through Acid Fast Bacilli stain or culture) at Instituto Nacional de Enfermedades Neoplasicas (INEN) a tertiary cancer center in Peru between January 2006 and September 2015. Patients were divided into two groups based on their HM diagnosis: Lymphomatous (n=32, 69.6%) and Leukemic/myeloma (n=14, 30.4%). Medical records were reviewed, including demographic data, pertinent laboratory data, Charlson Comorbidity Index (CCI), history of previous TB or contact with TB patients, ECOG, viral co-infections, treatment modality and response. Data was analyzed using T-Test and chi-square test, survival curves were estimated by Kaplan-Meier and comparison was done by log-rank test. Multivariate analysis for survival was performed with Cox proportional hazard regression.Results: Over the 10-year period we identified 46 adult patients with HM who subsequently developed culture confirmed TB during the observation period. Lymphomatous (L) and Leukemic/Myeloma (LM) subjects had a mean age of 57.03 and 40.93 respectively (p=0.009). LM patients had lower Hemoglobin (8.75 vs 11.18, p=0.003) and higher LDH levels (3134 vs 936, p=0.027). LM diagnosis was also associated with CCI scores less or equal to 4 (OR: 8.76, 95% CI [1.67, 45.88], p=0.005), negative HIV status (OR: 1.33, 95% CI [1.092, 1.629], p=0.004) and lower presence of constitutional symptoms (OR: 0.139, 95% CI [0.033, 0.578], p=0.004). Median times to development of Tuberculosis (dTB) were 4.9 months overall, 3.76 in the LM and 5.26 in the L group, the difference was not statistically significant (p=0.272). Mean overall survival (OS) were 67.94 for LM and 68.73 for L, difference was not statistically significant (p=0.56). In multivariate analysis for the entire cohort, age greater than 65, CCI of 5 or more, Absolute lymphocyte count <1000, LDH>1500, previous TB, presence of HIV and HTLV infection were associated with earlier dTB (see Table). Malnutrition and having an ECOG score of 3 or more were also associated but without statistical significance. HTLV infection and Absolute Lymphocyte Count <1000 were associated with mortality. TB related variables, including: Site of TB, Acid Fast Stain Status and Tuberculosis Treatment Regimen were not associated with mortality.Conclusions: We have analyzed the first cohort of HM patients with microbiologically confirmed TB in a high prevalence setting and have identified risk factors for development of TB including age, CCI, lymphopenia, high LDH, HIV and HTLV. This study will facilitate the identification of patients with HM at risk of developing TB. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb’s differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host’s antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.

Autophagy Induction as a Host-Directed Therapeutic Strategy against Mycobacterium tuberculosis Infection

Tuberculosis (TB), a bacterialinfectious disease caused by Mycobacterium tuberculosis (M.tb), which causes significant mortality in humans worldwide. Current treatment regimen involve the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homoeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB. However, current clinical knowledge on implementing autophagy activation by drugs or agents, as a stand-alone HDT or as an adjunct with antibiotics to treat human TB is insufficient. In recent years, many reports on high-throughput drug screening and measurement of autophagic flux by fluorescence, high-content microscopy, flow cytometry, microplate reader and immunoblotting have been published for the discovery of drugs that modulate autophagy. In this review, we discuss the commonly used chemical screening approaches in mammalian cells for the discovery of autophagy activating drugs against M.tbinfection. We also summarize the various autophagy-activating agents, both pre-clinical candidates and compounds approved for advanced clinical investigation during mycobacterial infection. Finally, we discuss the opportunities and challenges in using autophagy activation as HDT strategy to improve TB outcome and shorten treatment regimen.

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010-2020 Review.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern; herein, we have compiled drug-drug interaction reports, as well as efficacy reports for drug combinations studies involving antitubercular agents in clinical development.

Characteristics and Comorbidities at Start of Tuberculosis Treatment in Three Regions of the Philippines: The St-ATT Cohort

Background: Diabetes and undernutrition are common risk factors for tuberculosis (TB), associated with poor treatment outcomes and exacerbated by TB. Here we describe the characteristics and non-communicable multimorbidity (co-occurrence of 2 or more medical conditions) in Filipino adults at the time of initiating a new TB treatment regimen enrolled into the Starting Anti-TB Treatment (St-ATT) Cohort. Methods and Findings: Nine-hundred participants (69.6% male) were enrolled from 13 public health facilities in Metro Manila (N=184), Negros Occidental (N=372) and Cebu (N=344) within 5 days of starting treatment including 133 (14.8%) initiating the 9 month WHO shorter treatment regimen for multi-drug resistant TB (MDR-TB). Diabetes was defined as HbA1c ≥6.5% and/or current diabetes medication; hypertension as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg and/or current anti-hypertensive medication, anaemia as haemoglobin <11 g/dl and moderate/severe undernutrition as body-mass-index <17 kg/m2. The most common comorbidities were moderate/severe undernutrition 23.4% (210/899), diabetes 22.5% (199/881), hypertension 19.0% (164/864) and moderate/severe anaemia 13.5% (121/899). Fifty-eight percent had ≥1 of these comorbid conditions (496/847), with 17.1% having ≥2; the most common combination being diabetes and hypertension (N=57, 6.7%). Just over half of diabetes (54.8%) and hypertension (54.9%) was previously undiagnosed, and lack of glycemic control (HbA1c<8.0%) was common in those already on medication (N=50/73, 68.5%). MDR-TB treatment was associated with increased odds of diabetes (Adjusted odds ratio (AOR) = 2.48, 95% CI: 1.55-3.95); but decreased odds of hypertension (AOR=0.55, 95% CI: 0.39-0.78). HIV infection was only associated with anaemia (AOR=4.51, 95% CI: 1.01-20.1). Previous TB treatment was associated with moderate/severe undernutrition (AOR = 1.98, 95% CI: 1.40-2.80), as was increased duration of TB-symptoms before starting treatment and household food insecurity. No associations for sex, alcohol or tobacco use were observed. MDR-TB treatment was marginally associated with having ≥2 comorbidities (OR = 1.52, 95% CI: 0.97-2.39). Conclusions: TB treatment programmes need to consider planning for a large proportion of persons requiring diagnosis and management of comorbidities with the potential to adversely affect TB treatment outcomes and quality of life. Of the conditions examined here, dietary advice and nutritional management are considered usual components of comprehensive care.

Design of Multidrug-Resistant Tuberculosis Treatment Regimens Based on DNA Sequencing.

Comprehensive and reliable drug susceptibility testing (DST) is urgently needed to provide adequate treatment regimens for patients with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). We determined whether next-generation sequencing (NGS) analysis of Mycobacterium tuberculosis complex isolates and genes implicated in drug resistance can guide the design of effective MDR/RR-TB treatment regimens. NGS-based genomic DST predictions of M. tuberculosis complex isolates from MDR/RR-TB patients admitted to a TB reference center in Germany between 1 January 2015 and 30 April 2019 were compared with phenotypic DST results of mycobacteria growth indicator tubes (MGIT). Standardized treatment algorithms were applied to design individualized therapies based on either genomic or phenotypic DST results, and discrepancies were further evaluated by determination of minimal inhibitory drug concentrations (MICs) using Sensititre MYCOTBI and UKMYC microtiter plates. In 70 patients with MDR/RR-TB, agreement among 1048 pairwise comparisons of genomic and phenotypic DST was 86.3%; 76 (7.2%) results were discordant, and 68 (6.5%) could not be evaluated due to the presence of polymorphisms with yet unknown implications for drug resistance. Importantly, 549 of 561 (97.9%) predictions of drug susceptibility were phenotypically confirmed in MGIT, and 27 of 64 (42.2%) false-positive results were linked to previously described mutations mediating a low or moderate MIC increase. Virtually all drugs (99.0%) used in combination therapies that were inferred from genomic DST were confirmed to be susceptible by phenotypic DST. NGS-based genomic DST can reliably guide the design of effective MDR/RR-TB treatment regimens.