eSymposia | Tuberculosis: Science Aimed at Ending the Epidemic

Dec 2, 2020 ‐ Dec 4, 2020



Sessions

Combination Therapy to Combat Cavitary Tuberculosis

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Combination Therapy to Combat Cavitary Tuberculosis Monalisha Debnath1, Sujit Kumar Debnath2, Rohit Srivastava2,* 1Department of Electrical Engineering, Indian Institute of Technology, Kharagpur, West Bengal, India; 2,*Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India. *Corresponding author Tuberculosis continues to be a major threat to global health. Cavitation is a dangerous consequence of pulmonary tuberculosis associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance. Patients with cavity have a bacterial load of up to 1011 bacilli/gram, making it highly contagious. First-line and second-line therapy for tuberculosis are available. However, these drugs cannot reach the lungs from conventional dosage forms (tablets, capsules, and injection). So there is a research gap in the effective management of cavitary tuberculosis. There is a need for targeted delivery to concentrate the drug more in the lungs. By using inhalation therapy, we can improve the availability of anti-tubercular drugs in the cavitary site. However, these drugs cannot penetrate the cavity. One of the most promising reasons behind this type of TB is inflammation. Inflammation alters cell physiology. Hence, a combination of anti-inflammatory agents with the anti-tubercular drug will be a promising therapy for cavitary tuberculosis. In most cases, chemotherapy is not tissue-specific. Therefore, the drug is distributed throughout the body or non-specific. Thus, host-directed therapy will be another promising approach for this type of TB. Oxidative stress and overproduction of reactive oxygen species are the main key factor for the initiation of diseases like tuberculosis. Therefore proper regulation of ROS is highly essential, particularly in this type of TB. We have prepared the ethionamide (second-line anti-tubercular drugs) nanoparticles in the lab and modified them into a dry powder inhaler for pulmonary administration. In an animal study, this DPI was successfully delivered to the lung and sustained the action for more than 24 hr. Drug concentration in the lungs was maintained above minimum inhibitory concentration (MIC) for more than 12 hr. Hence, a twice-daily dose would able to maintain the drug concentration above MIC for 24 hr. A combination of ethionamide with other anti-inflammatory drugs or ROS regulatory agents will improve the treatment of cavitary tuberculosis.

Speaker(s):

Knowledge, attitude, and practice (KAP) survey of Zoonotic Tuberculosis prevention and associated determinants amongst Livestock Workers in Punjab, Pakistan.

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Knowledge, attitude, and practice (KAP) survey of Zoonotic Tuberculosis prevention and associated determinants amongst Livestock Workers in Punjab, Pakistan. Muhammad Yasir Zahoor1*, Ubaid-ur-Rehman Zia1, Abrar Hussain1, Muhammad Bilal1, Touseef Ahmed2, Sabir Hussain3, Muhammad Zain Akhtar4 Affiliations 1* Department of Epidemiology and Public Health, University of Veterinary and Animal Sciences, Lahore, Pakistan 2 Department of Biological Sciences, Texas Tech University, Lubbock, Texas, USA 3 Department of Infectious Diseases and Public Health. Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong 4 Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Pakistan Background Pakistan is among those countries having high Tuberculosis (TB) burden and Zoonotic TB is a neglected significant public health disease. This study aimed to assess the extent of knowledge and understanding of Zoonotic Tuberculosis disease spread and prevention among the herdsmen in Pakistan to provide the evidences for policy making in context of One Health. Methods A cross sectional survey (n=351) was conducted in 4 different regions of Punjab, Pakistan. Knowledge, attitude, and practices of herdsmen were assessed through a structured questionnaire. Bivariate and multivariate analysis was used to study the association between education level of respondents with different associated risk factors of zoonotic tuberculosis. Results Of 351 participants, 61%(n=214) were unaware about the zoonotic transmission of tuberculosis. Majority 78.3% (n=275) of respondents used to visit the hospital only when they get severely ill. Regarding the attitude towards disease, (35.9%(n=126)) herdsmen prefer to sell the infected animals to earn the instant profit and put the public at risk of getting zoonotic TB. Another high-risk activity under practice by the ever effected with TB was the use of unpasteurized milk ꭓ2(1) =6.146, p=0.013. The dung removal by naked hands was also found significantly associated with ever effected respondents ꭓ2(1) =11.024, p=0.0009. Majority of respondents 62.7% have not heard about the TB control program in Pakistan. The illiteracy had significant association with not knowing the TB control program (p

Speaker(s):

Both adaptive immunity and IL-1R1 dependent signals improve clearance of cytosolic virulent mycobacteria in vivo.

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Both adaptive immunity and IL-1R1 dependent signals improve clearance of cytosolic virulent mycobacteria in vivo. Authors Sanne van der Niet1, Maaike van Zon2, Karin de Punder2,3, Anita Grootemaat1, Sofie Rutten1, Simone Moorlag2, Diane Houben2, Astrid van der Sar4, Wilbert Bitter4, Roland Brosch5, Rogelio Hernandez Pando6, Maria T. Pena7, Eric A. Reits1, Katrin D. Mayer-Barber 8 and Nicole N. van der Wel1* Affiliations 1 Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre AMC, the Netherlands, 2 Netherlands Cancer Institute, The Netherlands, 3 Charité - Universitätsmedizin Berlin, Germany, 4 Amsterdam University Medical Centre VUMC, The Netherlands, 5 Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris, France, 6 National Institute of Medical Sciences and Nutrition, Mexico, 7 Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, National Hansen's Disease Programs, Baton Rouge, LA, USA 8 Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, USA. Abstract Mycobacterium tuberculosis infections claim more than a million lives each year and better treatments or vaccines are required. A crucial pathogenicity factor is translocation from the phago-lysosomes to the cytosol upon phagocytosis by macrophages. The translocation from the phago-lysosome into the cytosol is an ESX-1 dependent process as previously shown in vitro. Here we show that in vivo, mycobacteria also translocate to the cytosol but mainly when host immunity is compromised. We observed only low numbers of cytosolic bacilli in mice, armadillo, zebrafish and patient material infected with M. tuberculosis, M. marinum or M. leprae. In contrast, when innate or adaptive immunity was compromised, as in SCID or IL-1R1 deficient mice, a significant number of cytosolic M. tuberculosis bacilli were detected in lungs of infected mice. Taken together, the cytosolic localization of mycobacteria in vivo is controlled by adaptive immune responses as well as IL-1R1-mediated host resistance to M. tuberculosis.

Speaker(s):

Current trend of an epidemic MDR-Mycobacterium tuberculosis strain unveiled by an allele-specific multiplex PCR

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Current trend of an epidemic MDR-Mycobacterium tuberculosis strain unveiled by an allele-specific multiplex PCR Abstract. The so-called Rb strain has long been the third most prevalent multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strain in Argentina, following the M and Ra strains. As we did with these latter two, we now developed a multiplex PCR targeting Rb-specific SNPs identified by WGS. It was applied to identify new MDR-TB cases caused by the Rb strain in 2018-2019. Herein we found that the current incidence of Rb-associated MDR-tuberculosis increased compared to the data from the previous decade. In contrast with M and Ra strains, Rb is geographically widespread within the country. This strain still prevails in HIV-infected transgender sex workers, its most conspicuous target population. This new strain-specific multiplex PCR enhanced our toolkit for the rapid and low-cost surveillance of conspicuous MDR-Mtb strains. Authors. Noemí Yokobori(a, b, c), Laura Pérez-Lago(a, d), Roxana Paul(b), Romina Grossich(b), Ingrid Weinmeyer(b), Norberto Símboli(b), Beatriz López(b), Viviana Ritacco(b,c,e), Darío García De Viedma(d, e, f) (a)These authors contributed equally to this work as firts authors. (b)Instituto Nacional de Enfermedades Infecciosas ANLIS, Buenos Aires, Argentina. (c)Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina. (d)Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. (e)CIBER Enfermedades Respiratorias, CIBERES, Madrid, Spain. (f)These authors contributed equally to this work as senior authors

Speaker(s):
  • Noemi Yokobori, PhD, Instituto Nacional de Enfermedades Infecciosas, ANLIS

Functional Characterization of the Transcriptional response to DNA damage in mycobacteria

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Functional Characterization of the Transcriptional response to DNA damage in mycobacteria Authors: Oyindamola Adefisayo, Michael Glickman Affiliations: Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center Abstract: It is critical to understand the mycobacterial DNA damage response (DDR) due to its role in mutagenesis, the ultimate cause of antibiotic resistance, and in resisting DNA damage inflicted by host immunity. Mycobacteria encode two transcriptional DDR pathways that control the expression of multiple genes essential for DNA repair and mutagenesis. The two pathways are controlled by the activator PafBC and the LexA repressor. Although the regulons controlled by these systems are defined, the division of labor between them for repair and mutagenesis, and the activating signal for the PafBC pathway, are unknown. To address these questions, we ablated the PafBC pathway (, the SOS pathway (through an uncleavable lexA S167A point mutation), or both, along with ablation of recA, which has been used in literature as a proxy for the SOS pathway in Mycobacterium smegmatis (Msmeg). We used these strains to analyze the division of labor between these pathways in response to multiple DNA damaging agents, including quinolones, UV light and mitomycin C. Transcriptional profiling by RNA sequencing in response to both UV and ciprofloxacin induced DNA damage confirmed prior reports that PafBC controls a larger transcriptional program than LexA. However, ablation of the SOS response reveals a dominant role for this system in sensitivity to killing by DNA damage and mutagenesis. In addition, although SOS deficient bacteria are more sensitive to UV damage than PafBC deficient bacteria, only double PafBC/SOS deficiency phenocopies loss of RecA, indicating functional redundancy between the pathways. In contrast to prior studies that equated ablation of RecA with loss of the SOS pathway, we find that the ablation of recA actually closely phenocopies the double pafBC/lexA S167A strain, particularly when comparing DNA damage induced gene expression. Additionally, transcriptional profiling and RecA protein expression in both M. smegmatis and M. tuberculosis reveal that quinolone stress may be a preferential inducer of the PafBC pathway. Taken together, our results show that although the PafBC pathway controls a larger transcriptional regulon, the SOS pathway plays a dominant role in DNA damage survival and mutagenesis. Our studies identify quinolone stress as an inducer of PafBC dependent gene expression, potentially providing a window into the activating signal of the PafBC pathway. Finally, our data indicate that intact RecA function is required for the full expression of both the SOS and PafBC pathways.

Speaker(s):

The antimycobacterial, cytotoxic and hepatoprotective effects of some Menispermaceae species

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

The antimycobacterial, cytotoxic and hepatoprotective effects of some Menispermaceae species R.T. Akande1,2, I. Famuyide1, A. Aro3, S.M. Nkadimeng1, T. Hlokwe4, L.J. McGaw1 1Phytomedicine Programme, Department of Paraclinical sciences, Faculty of Veterinary Sciences, University of Pretoria, Pretoria, South Africa. 2Nigeria Atomic Energy Commission, Abuja, Nigeria. 3Department of Agriculture and Animal Health, College of Agriculture and Environmental Sciences, University of South Africa, Florida, South Africa. 4Bacteriology Section, Agricultural Research Council—Onderstepoort Veterinary Institute, Onderstepoort, Pretoria, South Africa. Tuberculosis (TB) is an infectious disease of worldwide occurrence. Millions of people are infected and fall sick annually. The rate of mortality by tuberculosis is much higher than any other bacterial infections. Some species of the Menispermaceae family are used locally for cough and tuberculosis related symptoms. This study was carried out to verify the traditional use of the plants. In this study, hot water was used for extraction of the dried, ground plant material. The antimycobacterial effects of Cissampelos owariensis (whole plant), Cissampelos mucronata (leaf and stem) and Tinospora fragosa (aerial parts) were evaluated using a two-fold broth dilution method against non-pathogenic and pathogenic mycobacterial strains. Cytotoxicity of the extracts was determined against African monkey kidney (Vero) cells using an MTT assay. The hepatoprotective effects was evaluated using rifampicin and acetaminophen as toxicants against HepG2 liver cells. The hot water extracts had minimum inhibitory concentration (MIC) values of 12.5 – 940 µg/ml. The extracts had low cytotoxicity to Vero cells (˃100 µg/ml) and were protective on the damaged-induced liver cells. Further studies are continuing on other biological effects of the extracts.

Speaker(s):

Evaluation of the Properties of Rifampicin-Loaded Solid Lipid Microparticles Based on Moringa oleifera oil and Phospholipon 90G Admixtures

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Evaluation of the Properties of Rifampicin-Loaded Solid Lipid Microparticles Based on Moringa oleifera oil and Phospholipon 90G Admixtures Evaluation of the Properties of Rifampicin-Loaded Solid Lipid Microparticles Based on Moringa oleifera oil and Phospholipon 90G Admixtures *Salome A. Chime, Echezona O. Ogudiegwu and Ikechukwu V. Onyishi Department of Pharmaceutical Technology and Industrial Pharmacy, University of Nigeria, Nsukka 410001, Nigeria *Corresponding author: Tel.: +2348061329790 Fax: +234-42-771709 E-mail address: salome.chime@unn.edu.ng Abstract Context: Rifampicin is one of the most effective antitubercular agents, however, it suffers from many drawbacks such as, short half-life, adverse effects, pH-dependent degradation, and bioavailability problems. The degradation of the Rifampicin in acidic pH of the stomach depends on the initial amount of drug released in the stomach. Hence formulations designed as sustained release systems are of immense benefit in order to release the drug in intestinal pH and hence, circumvent degradation in gastric pH of 1.2. Aim: The aim of the work was to formulate sustained release rifampicin-loaded solid lipid microparticles (SLMs) using structured lipid matrices based on Moringa oil (MO) and Phospholipon 90G (P90G) for effective treatment of tuberculosis. Materials and Methods: Rifampicin-loaded and unloaded SLMs were formulated by melt homogenization and characterized for particle morphology and size, encapsulation efficiency (EE%), pH stability, stability in simulated gastric fluid (SGF, pH 1.2), minimum inhibitory concentration (MIC) and in vitro release. In vivo release was studied in Wistar rats. Results: Rifampicin-loaded SLMs had particle size range of 32.50 ± 2.10 to 34.0 ± 8.40 μm, highest EE% of 87.6 % and showed stable pH. SLMs had good sustained release properties with about 77.1 % release at 12 h in phosphate buffer (pH 6.8) and 80.3 % drug release at 12 h in simulated intestinal fluid (SIF, pH 7.4). SLMs exhibited 48.51 % degradation of rifampicin in SGF at 3 h, while rifampicin pure sample had 95.5 % degradation. Formulations exhibited MIC range of 0.781 to 1.562, 31.25 to 62.5 and 6.25 to 12.5 μg/ml against Salmonella typhi, Escherichia coli, and Bacillus subtilis respectively and had higher in vivo absorption than the reference rifampicin (p < 0.05). Conclusion: Rifampicin-loaded SLMs exhibited good in vitro stability in SGF and showed drug release profiles which indicated that they could be used once daily for the treatment tuberculosis. Keywords: Moringa oil; tuberculosis; in vivo release; lipid absorption, rifampicin degradation.

Speaker(s):
  • Salome A. Chime, PhD, Department of Pharmaceutical Technology and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria

Drivers and sites of variable DNA methylation in Mycobacterium tuberculosis clinical isolates

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Drivers and sites of variable DNA methylation in Mycobacterium tuberculosis clinical isolates 1Samuel J. Modlin, 1Derek Conkle-Gutierrez, 1Calvin Kim, 1Scott N. Mitchell, 1Christopher Morrissey, 2Brian C. Weinrick, 3William R. Jacobs Jr., 1Sarah M. Ramirez-Busby, 1,4Sven E. Hoffner, and 1Faramarz Valafar* 1Laboratory for Pathogenesis of Clinical Drug Resistance and Persistence, San Diego State University, San Diego, CA, USA 2Trudeau Institute, Saranac Lake, NY, USA 3Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA 4Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden Whole genome sequencing has been transformative for our understanding of genetic diversity in the Mycobacterium tuberculosis complex (MTBC). Yet there has been limited description of epigenomic diversity in the MTBC. We analyzed sequencing kinetics of single-molecule real-time sequencing data to fully assemble DNA methylomes from 93 phylogeographically diverse MTBC clinical isolates. We identify drivers and sites of methylomic diversity across the MTBC. First, through heterogeneity analysis we identify and describe "Intercellular mosaic methylation" (IMM), a form of prokaryotic DNA methylation heterogeneity distinct from established forms. Though rare overall, constitutive IMM is nearly ubiquitous in Beijing isolates, suggesting IMM might confer an adaptive advantage to the Beijing sublineage. Second, integrative analysis of methylomes and transcriptional data revealed widespread promoter methylation in MTBC, including many clinically important genes, and evidence for DNA methylation directly influencing promoter strength. Third, comparing within and across methylomes identified 351 sites that are especially variable across isolates which, when considered alongside the apparent effect of promoter methylation on transcription, suggest these sites may confer epigenomic-driven phenotypic variability across clinical isolates. This dataset and our findings provide a basis for future work delineating the roles of DNA adenine methylation in MTBC physiology and adaptive evolution.

Speaker(s):

Integration of genetic and transcriptional profiles of innate cells to decipher mechanisms of TB susceptibility

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Integration of genetic and transcriptional profiles of innate cells to decipher mechanisms of TB susceptibility Sara Suliman1, Maria Arcelus-Gutierrez1,2,3,4,5, Samira Asgari1,2,3,4,5, Sarah K. Iwany1, Kattya Lopez Tamara1,6, Yang Luo1,2,3,4,5, Aparna Nathan1,2,3,4,5, Zibiao Zhang7, Segundo R León6, Roger I Calderon6, Leonid Lecca6, Megan B. Murray7, Ildiko Van Rhijn1,8, Soumya Raychaudhuri1,2,3,4,5,9, and D. Branch Moody1 1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Broad Institute of MIT and Harvard, Cambridge, MA, USA; 4Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA 5Center for Data Sciences, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; 6Socios En Salud Sucursal Peru, Lima, Peru; 7Department of Global Health and Social Medicine, and Division of Global Health Equity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 8Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands 9Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK. Most people infected with Mycobacterium tuberculosis (Mtb) never develop TB disease, suggesting host-specific risk factors for disease progression. Transcriptional profiling of samples from TB patients and Mtb-exposed controls identified innate pathways associated with progression to TB disease. However, few published studies integrate genetic variation with transcriptional profiles to decipher mechanisms of TB pathogenesis. We sought to determine how genetic polymorphisms influence expression of key innate response genes between individuals at high and low risk of progression to TB. From a prospective Peruvian cohort of household contacts of TB patients, we re-recruited fully genotyped former progressors (n=68) and non-progressors (n=67) and stored cryopreserved peripheral blood mononuclear cell samples. We generated monocyte-derived dendritic cells and macrophages by differentiating sorted monocytes in granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL4), or macrophage colony-stimulating factor (M-CSF), respectively. Samples were analyzed by low-input RNA-sequencing and flow cytometry. We analyzed the impact of genetic polymorphisms on expression of key target genes in an expression quantitative trait loci (eQTL) study. We identified 433 and 355 eQTL events in DCs and macrophages, respectively, 76 of which were unique to one cell type. In addition, we identified a novel interaction between a single nucleotide polymorphism rs2562754 and TB status with expression of FAH, the gene encoding for Fumaryl Acetoacetate Hydrolase, which mediates tyrosine catabolism. This eQTL analysis highlights under-explored candidate TB susceptibility pathways, which are now being functionally validated using CRISPR-based gene editing.

Speaker(s):

Optimization of Indolecarboxamides Inhibiting MmpL3 in Mycobacterium Tuberculosis

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Optimization of Indolecarboxamides Inhibiting MmpL3 in Mycobacterium Tuberculosis Authors: Sauvik Samanta (a), Candice Soares de Melo (a), Sandeep R. Ghorpade (a), Vinayak Singh (b), Chandramohan Bathula (a), Lebu Taleli (a), Sanjit Das (a), Stephen Fienberg (a), Nina Lawrence (c), Mathew Njoroge (c), Natalie Hawryluk (d), Stacie Canan (d), Dale Robinson (d), Geraldine Hernandez (d), Yixing Shen (d), Joseph Camardo (e), Vikram Khetani (e), Ben Gold (f), Carl Nathan (f), Dirk Schnappinger (f), Tanya Parish (g), Gregory S. Basarab (a,c), Leslie Street (a), Charles J. Eyermann (a), and Kelly Chibale (a,h)* Affiliations: (a) Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; (b) Drug Discovery and Development Centre (H3D), Institute of Infectious Disease and Molecular Medicine University of Cape Town, Rondebosch 7701, South Africa; (c) Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa; (d) Celgene Global Health, San Diego, California, United States of America; (e) Celgene Global Health, Summit, New Jersey, United States of America; (f) Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States of America; (g) Infectious Disease Research Institute, Seattle, United States; (h) South African Medical Research Council Centre for Tuberculosis Research / DST/NRF Abstract body: With the growing incidence of multi- and extensively drug resistant tuberculosis (TB), there is a continuous need to identify multiple novel and mechanistically distinct anti-TB drugs possessing reduced liabilities for investigation in new TB drug regimens.1 The mycobacterial membrane protein large 3 (MmpL3) is an inner membrane protein that transports mycolic acids, in the form of their precursors trehalose monomycolates, from the cytoplasm to the periplasmic space, where mycolic acids can then be used in assembly of the mycobacterial outer membrane. Inactivation of MmpL3 weakens the bacterial cell wall and impacts the viability and virulence of M. tuberculosis (Mtb), making it an attractive target for anti-TB drugs. The phenotypic screening of a diversity library from Celgene Global Health against replicating Mtb led to the identification of the indole-2-carboxamide hits with potent antimycobacterial activity, a favorable selectivity index over mammalian cytotoxicity, good permeability and an improved lipophilicity and structural diversity over literature indolecarboxamides. MmpL3 was confirmed as a target of indolecarboxamides by generating spontaneous-resistant mutants followed by whole-genome sequencing, and the observed hypersusceptibility of tested compounds to M. tuberculosis upon mmpL3 silencing. Encouraged by this, we initiated structure-activity relationship (SAR) investigations and optimization of series issues such as poor solubility and hERG inhibition, to establish scope of progression of indolecarboxamides towards a preclinical candidate nomination. References 1. Zumla, A. I.; Gillespie, S. H.; Hoelscher, M.; Philips, P. P. J.; Cole, S. T.; Abubakar, I.;McHugh, T. D.; Schito, M.; Maeurer, M.; Nunn, A. J. The Lancet Infectious Diseases 2014, 14, 327-340. 2. Hett, E.C.; Rubin, E.J. Microbiol. Mol. Biol. Rev. 2008, 72, 126–156.

Speaker(s):
Print Certificate
Completed on: token-completed_on
Print Transcript
Please select the appropriate credit type:
/
test_id: 
credits: 
completed on: 
rendered in: 
* - Indicates answer is required.
token-content

token-speaker-name
token-index
token-content
token-index
token-content
token-index
token-content
token-index
token-content
token-index
token-content
token-index
token-content
/
/
token-index
token-content
token-index
token-content