scholarly journals Novel Antimicrobials from Uncultured Bacteria Acting against Mycobacterium tuberculosis

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Jeffrey Quigley ◽  
Aaron Peoples ◽  
Asel Sarybaeva ◽  
Dallas Hughes ◽  
Meghan Ghiglieri ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Protein Secretion ◽  
Specific Activity ◽  
Therapeutic Options ◽  
Content Type ◽  
Natural Product Discovery ◽  
Uncultured Bacteria ◽  
New Compounds ◽  
Drug Resistant Strains

ABSTRACT Mycobacterium tuberculosis, which causes tuberculosis (TB), is estimated to infect one-third of the world’s population. The overall burden and the emergence of drug-resistant strains of Mycobacterium tuberculosis underscore the need for new therapeutic options against this important human pathogen. Our recent work demonstrated the success of natural product discovery in identifying novel compounds with efficacy against Mycobacterium tuberculosis. Here, we improve on these methods by combining improved isolation and Mycobacterium tuberculosis selective screening to identify three new anti-TB compounds: streptomycobactin, kitamycobactin, and amycobactin. We were unable to obtain mutants resistant to streptomycobactin, and its target remains to be elucidated. We identify the target of kitamycobactin to be the mycobacterial ClpP1P2C1 protease and confirm that kitamycobactin is an analog of the previously identified compound lassomycin. Further, we identify the target of amycobactin to be the essential protein secretion pore SecY. We show further that amycobactin inhibits protein secretion via the SecY translocon. Importantly, this inhibition is bactericidal to nonreplicating Mycobacterium tuberculosis. This is the first compound, to our knowledge, that targets the Sec protein secretion machinery in Mycobacterium tuberculosis. This work underscores the ability of natural product discovery to deliver not only new compounds with activity against Mycobacterium tuberculosis but also compounds with novel targets. IMPORTANCE Decreasing discovery rates and increasing resistance have underscored the need for novel therapeutic options to treat Mycobacterium tuberculosis infection. Here, we screen extracts from previously uncultured soil microbes for specific activity against Mycobacterium tuberculosis, identifying three novel compounds. We further define the mechanism of action of one compound, amycobactin, and demonstrate that it inhibits protein secretion through the Sec translocation machinery.

scholarly journals Molecular Characterization of Multidrug-Resistant Mycobacterium tuberculosis Isolated in Nepal

2012 ◽  
Vol 56 (6) ◽  
pp. 2831-2836 ◽  
Author(s):  
Ajay Poudel ◽  
Chie Nakajima ◽  
Yukari Fukushima ◽  
Haruka Suzuki ◽  
Basu Dev Pandey ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Promoter Region ◽  
Multidrug Resistant ◽  
Content Type ◽  
Molecular Tests ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Substitution Mutations ◽  
Drug Resistant Strains

ABSTRACTDespite the fact that Nepal is one of the first countries globally to introduce multidrug-resistant tuberculosis (MDR-TB) case management, the number of MDR-TB cases is continuing to rise in Nepal. Rapid molecular tests applicable in this setting to identify resistant organisms would be an effective tool in reversing this trend. To develop such tools, information about the frequency and distribution of mutations that are associated with phenotypic drug resistance inMycobacterium tuberculosisis required. In the present study, we investigated the prevalence of mutations inrpoBandkatGgenes and theinhApromoter region in 158M. tuberculosisisolates (109 phenotypically MDR and 49 non-MDR isolates collected in Nepal) by DNA sequencing. Mutations affecting the 81-bp rifampin (RIF) resistance-determining region (RRDR) ofrpoBwere identified in 106 of 109 (97.3%) RIF-resistant isolates. Codons 531, 526, and 516 were the most commonly affected, at percentages of 58.7, 15.6, and 15.6%, respectively. Of 113 isoniazid (INH)-resistant isolates, 99 (87.6%) had mutations in thekatGgene, with Ser315Thr being the most prevalent (81.4%) substitution. Mutations in theinhApromoter region were detected in 14 (12.4%) INH-resistant isolates. The results from this study provide an overview of the current situation of RIF and INH resistance inM. tuberculosisin Nepal and can serve as a basis for developing or improving rapid molecular tests to monitor drug-resistant strains in this country.

scholarly journals In Vitro Activity and MIC of Sitafloxacin against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis Isolated in Thailand

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Manoon Leechawengwongs ◽  
Therdsak Prammananan ◽  
Sarinya Jaitrong ◽  
Pamaree Billamas ◽  
Nampueng Makhao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Concentration ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT New fluoroquinolones (FQs) have been shown to be more active against drug-resistant Mycobacterium tuberculosis strains than early FQs, such as ofloxacin. Sitafloxacin (STFX) is a new fluoroquinolone with in vitro activity against a broad range of bacteria, including M. tuberculosis. This study aimed to determine the in vitro activity of STFX against all groups of drug-resistant strains, including multidrug-resistant M. tuberculosis (MDR M. tuberculosis), MDR M. tuberculosis with quinolone resistance (pre-XDR), and extensively drug-resistant (XDR) strains. A total of 374 drug-resistant M. tuberculosis strains were tested for drug susceptibility by the conventional proportion method, and 95 strains were randomly submitted for MIC determination using the microplate alamarBlue assay (MABA). The results revealed that all the drug-resistant strains were susceptible to STFX at a critical concentration of 2 μg/ml. Determination of the MIC90s of the strains showed different MIC levels; MDR M. tuberculosis strains had a MIC90 of 0.0625 μg/ml, whereas pre-XDR and XDR M. tuberculosis strains had identical MIC90s of 0.5 μg/ml. Common mutations within the quinolone resistance-determining region (QRDR) of gyrA and/or gyrB did not confer resistance to STFX, except that double mutations of GyrA at Ala90Val and Asp94Ala were found in strains with a MIC of 1.0 μg/ml. The results indicated that STFX had potent in vitro activity against all the groups of drug-resistant M. tuberculosis strains and should be considered a new repurposed drug for treatment of multidrug-resistant and extensively drug-resistant TB.

scholarly journals Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4457-4463 ◽  
Author(s):  
Benoit Lechartier ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Drug Resistant Strains ◽  
Transfer Chain

ABSTRACTClofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. InMycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM againstM. tuberculosisand found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergisticin vitrowith benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was testedin vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains ofM. tuberculosis.

scholarly journals Oxadiazoles Have Butyrate-Specific Conditional Activity against Mycobacterium tuberculosis

2016 ◽  
Vol 60 (6) ◽  
pp. 3608-3616 ◽  
Author(s):  
Julie V. Early ◽  
Allen Casey ◽  
Maria Angeles Martinez-Grau ◽  
Isabel C. Gonzalez Valcarcel ◽  
Michal Vieth ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Carbon Source ◽  
Mammalian Cells ◽  
Sole Carbon Source ◽  
Specific Activity ◽  
Antitubercular Activity ◽  
Content Type ◽  
Phenotypic Screen

Mycobacterium tuberculosisis a global pathogen of huge importance which can adapt to several host niche environments in which carbon source availability is likely to vary. We developed and ran a phenotypic screen using butyrate as the sole carbon source to be more reflective of the host lung environment. We screened a library of ∼87,000 small compounds and identified compounds which demonstrated good antitubercular activity againstM. tuberculosisgrown with butyrate but not with glucose as the carbon source. Among the hits, we identified an oxadiazole series (six compounds) which had specific activity againstM. tuberculosisbut which lacked cytotoxicity against mammalian cells.

Anti-HIV natural product (+)-calanolide A is active against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis

2004 ◽  
Vol 12 (5) ◽  
pp. 1199-1207 ◽  
Author(s):  
Ze-Qi Xu ◽  
William W Barrow ◽  
William J Suling ◽  
Louise Westbrook ◽  
Esther Barrow ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Anti Hiv ◽  
Calanolide A

scholarly journals In VitroSusceptibility of Mycobacterium tuberculosis Isolates to an Oral Carbapenem Alone or in Combination with β-Lactamase Inhibitors

2014 ◽  
Vol 58 (11) ◽  
pp. 7010-7014 ◽  
Author(s):  
Yasuhiro Horita ◽  
Shinji Maeda ◽  
Yuko Kazumi ◽  
Norio Doi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Human Blood ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACTWe evaluated the antituberculosis (anti-TB) activity of five β-lactams alone or in combination with β-lactamase inhibitors against 41 clinical isolates ofMycobacterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Of those, tebipenem, an oral carbapenem, showed the most potent anti-TB activity against clinical isolates, with a MIC range of 0.125 to 8 μg/ml, which is achievable in the human blood. More importantly, in the presence of clavulanate, MIC values of tebipenem declined to 2 μg/ml or less.

scholarly journals Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum

2020 ◽  
Vol 84 (4) ◽  
Author(s):  
Alexandra E. Chirakos ◽  
Ariane Balaram ◽  
William Conrad ◽  
Patricia A. Champion
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Chronic Disease ◽  
Protein Secretion ◽  
Molecular Mechanisms ◽  
Salt Water ◽  
Secretion System ◽  
Mycobacterium Marinum ◽  
Content Type

SUMMARY Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. Mycobacterium tuberculosis causes both acute and chronic human tuberculosis. Environmentally acquired nontubercular mycobacteria (NTM) cause chronic disease in humans and animals. Not surprisingly, NTM and M. tuberculosis often use shared molecular mechanisms to survive within the host. The ESX-1 system is a specialized secretion system that is essential for virulence and is functionally conserved between M. tuberculosis and Mycobacterium marinum. M. marinum is an NTM found in both salt water and freshwater that is often used to study mycobacterial virulence. Since the discovery of the secretion system in 2003, the use of both M. tuberculosis and M. marinum has defined the conserved molecular mechanisms underlying protein secretion and the lytic and regulatory activities of the ESX-1 system. Here, we review the trajectory of the field, including key discoveries regarding the ESX-1 system. We highlight the contributions of M. marinum studies and the conserved and unique aspects of the ESX-1 secretion system.

scholarly journals High-Content Screening Technology Combined with a Human Granuloma Model as a New Approach To Evaluate the Activities of Drugs against Mycobacterium tuberculosis

2014 ◽  
Vol 59 (1) ◽  
pp. 693-697 ◽  
Author(s):  
Mayra Silva-Miranda ◽  
Euloge Ekaza ◽  
Adrien Breiman ◽  
Karim Asehnoune ◽  
David Barros-Aguirre ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
High Content Screening ◽  
Drug Resistant ◽  
Major Health Problem ◽  
Major Health ◽  
New Approach ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACTTuberculosis remains a major health problem due to the emergence of drug-resistant strains ofMycobacterium tuberculosis. Some models have provided valuable information about drug resistance and efficacy; however, the translation of these results into effective human treatments has mostly proven unsuccessful. In this study, we adapted high-content screening (HCS) technology to investigate the activities of antitubercular compounds in the context of anin vitrogranuloma model. We observed significant shifts in the MIC50s between the activities of the compounds under extracellular and granuloma conditions.

anti-HIV Natural Product (+)-Calanolide A Is Active Against Both Drug-Susceptible and Drug-Resistant Strains of Mycobacterium tuberculosis.

ChemInform ◽  
2004 ◽  
Vol 35 (29) ◽  
Author(s):  
Ze-Qi Xu ◽  
William W. Barrow ◽  
William J. Suling ◽  
Louise Westbrook ◽  
Esther Barrow ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Anti Hiv ◽  
Calanolide A

scholarly journals In Vitro Efficacies, ADME, and Pharmacokinetic Properties of Phenoxazine Derivatives Active against Mycobacterium tuberculosis

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Lloyd Tanner ◽  
Joanna C. Evans ◽  
Ronnett Seldon ◽  
Audrey Jordaan ◽  
Digby F. Warner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Infected Animal ◽  
Mechanisms Of Action ◽  
Drug Resistant ◽  
Content Type ◽  
Pharmacokinetic Properties ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a leading infectious killer globally, demanding the urgent development of faster-acting drugs with novel mechanisms of action. Riminophenazines such as clofazimine are clinically efficacious against both drug-susceptible and drug-resistant strains of M. tuberculosis. We determined the in vitro anti-M. tuberculosis activities, absorption, distribution, metabolism, and excretion properties, and in vivo mouse pharmacokinetics of a series of structurally related phenoxazines. One of these, PhX1, displayed promising drug-like properties and potent in vitro efficacy, supporting its further investigation in an M. tuberculosis-infected animal model.

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