- Thiazomycin, nocathiacin and analogs show strong activity against clinical strains of drug-resistant Mycobacterium tuberculosis. [Journal Article]
- JAJ Antibiot (Tokyo) 2017 Jan 18
- Thiazolyl peptides are a class of natural products with potent Gram-positive antibacterial activities. Lack of aqueous solubility precluded this class of compounds from advancing to clinical evaluati...
Thiazolyl peptides are a class of natural products with potent Gram-positive antibacterial activities. Lack of aqueous solubility precluded this class of compounds from advancing to clinical evaluations. Nocathiacins and thiazomycins are sub-classes of thiazolyl peptides that are endowed with structural features amenable for chemical modifications. Semi-synthetic modifications of nocathiacin led to a series of analogs with improved water solubility, while retaining potency and antibacterial spectrum. We studied the activities of a selection of two natural products (nocathiacin and thiazomycin) as well as seven polar semi-synthetic analogs against twenty clinical strains of Mycobacterium tuberculosis with MDR phenotypes. Two compounds show useful activity against H37Rv strain with MIC values ⩽1 μM, two (⩽0.5 μm) and three (⩽10 μm). These two derivatives showed MIC values ⩽2.5 μm against most of the 20 MDR strains regardless their resistance profile. Specifically, these lack cross-resistance to rifampicin, isoniazid and moxifloxacin.The Journal of Antibiotics advance online publication, 18 January 2017; doi:10.1038/ja.2016.165.
- Resistance to thiacetazone derivatives active against Mycobacterium abscessus involves mutations in the MmpL5 transcriptional repressor MAB_4384. [Journal Article]
- AAAntimicrob Agents Chemother 2017 Jan 17
- Available chemotherapeutic options are very limited against Mycobacterium abscessus, which imparts a particular challenge in the treatment of cystic fibrosis (CF) patients infected with this rapid-gr...
Available chemotherapeutic options are very limited against Mycobacterium abscessus, which imparts a particular challenge in the treatment of cystic fibrosis (CF) patients infected with this rapid-growing mycobacterium. New drugs are urgently needed against this emerging pathogen, but the discovery of active chemotypes has not been performed intensively. Interestingly, however, the repurposing of thiacetazone (TAC), a drug once used to treat tuberculosis, has increased following the deciphering of its mechanism of action and the detection of significantly more potent analogues. We, therefore, report studies performed on a library of 38 TAC-related derivatives, previously evaluated for their antitubercular activity. Several compounds, including D6, D15 and D17, were found to exhibit potent activity in vitro against M. abscessus, Mycobacterium massiliense and Mycobacterium bolletii clinical isolates from CF and non-CF patients. Similarly to TAC in M. tuberculosis, the three analogues act as pro-drugs in M. abscessus, requiring bioactivation by the EthA enzyme, MAB_0985. Importantly, mutations in the transcriptional TetR repressor MAB_4384, with concomitant upregulation of the divergently oriented adjacent genes encoding an MmpS5/MmpL5 efflux pump system, accounted for high cross-resistance levels among all three compounds. Overall, this study uncovered a new mechanism of drug resistance in M. abscessus and demonstrated that simple structural optimization of the TAC scaffold can lead to the development of new drug candidates against M. abscessus infections.
- Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance. [Journal Article]
- NGenNat Genet 2017 Jan 16
- Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome se...
Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.
- Identification of unique essential proteins from a M. tuberculosis F15/LAM4/KZN phage secretome library. [Journal Article]
- PDPathog Dis 2017 Jan 12
- Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis disease (TB), the leading cause of death from bacterial infection worldwide. Although treatable, the resurgence of multi- and e...
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis disease (TB), the leading cause of death from bacterial infection worldwide. Although treatable, the resurgence of multi- and extensively-drug resistance TB is a major setback for the fight against TB globally. Consequently, there is an urgent need for new Mtb derived biomarkers for use in the design of new drugs and rapid point-of-care diagnostic or prognostic tools for management of TB transmission. Therefore, the present study aimed to identify unique Mtb secreted proteins from the extensively drug resistant Mtb F15/LAM4/KZN phage secretome library. A whole genome library was constructed using genomic DNA fragments of Mtb F15/LAM4/KZN strain. A phage secretome sub-library of 8 × 10(3) clones was prepared and phage DNA was sequenced from 120 randomly selected clones. DNA sequence BLAST analysis identified 86 open reading frames. Using bioinformatics tools and databases, ten proteins essential for in vivo growth and survival of Mtb (Nrp, PssA, MmpL5, SirA, GatB, EspA, TopA, EccCa1, Rv1634 and Rv3103c). Proteins essential for growth and survival of Mtb during infection have potential application in the development of diagnostic tools, new drugs and vaccines. Further studies will be conducted to evaluate their potential application in the fight against TB.
- [Contribution of microbiology in the diagnosis of tuberculosis in Castile and León (Spain): Findings of the GRUMICALE 2013 study]. [Journal Article]
- EIEnferm Infecc Microbiol Clin 2017 Jan 10
- CONCLUSIONS: An adequate collection of microbiological information is essential to determine the epidemiology of TB in our region.
- The Minimal Unit of Infection: Mycobacterium tuberculosis in the Macrophage. [Journal Article]
- MSMicrobiol Spectr 2016; 4(6)
- The interaction between Mycobacterium tuberculosis and its host cell is highly complex and extremely intimate. Were it not for the disease, one might regard this interaction at the cellular level as ...
The interaction between Mycobacterium tuberculosis and its host cell is highly complex and extremely intimate. Were it not for the disease, one might regard this interaction at the cellular level as an almost symbiotic one. The metabolic activity and physiology of both cells are shaped by this coexistence. We believe that where this appreciation has greatest significance is in the field of drug discovery. Evolution rewards efficiency, and recent data from many groups discussed in this review indicate that M. tuberculosis has evolved to utilize the environmental cues within its host to control large genetic programs or regulons. But these regulons may represent chinks in the bacterium's armor because they include off-target effects, such as the constraint of the metabolic plasticity of M. tuberculosis. A prime example is how the presence of cholesterol within the host cell appears to limit the ability of M. tuberculosis to fully utilize or assimilate other carbon sources. And that is the reason for the title of this review. We believe firmly that, to understand the physiology of M. tuberculosis and to identify new drug targets, it is imperative that the bacterium be interrogated within the context of its host cell. The constraints induced by the environmental cues present within the host cell need to be preserved and exploited. The M. tuberculosis-infected macrophage truly is the "minimal unit of infection."
- Mycobacterium bovis and Other Uncommon Members of the Mycobacterium tuberculosis Complex. [Journal Article]
- MSMicrobiol Spectr 2016; 4(6)
- Since its discovery by Theobald Smith, Mycobacterium bovis has been a human pathogen closely related to animal disease. At present, M. bovis tuberculosis is still a problem of importance in many coun...
Since its discovery by Theobald Smith, Mycobacterium bovis has been a human pathogen closely related to animal disease. At present, M. bovis tuberculosis is still a problem of importance in many countries and is considered the main cause of zoonotic tuberculosis throughout the world. Recent development of molecular epidemiological tools has helped us to improve our knowledge about transmission patterns of this organism, which causes a disease indistinguishable from that caused by Mycobacterium tuberculosis. Diagnosis and treatment of this mycobacterium are similar to those for conventional tuberculosis, with the important exceptions of constitutive resistance to pyrazinamide and the fact that multidrug-resistant and extremely drug-resistant M. bovis strains have been described. Among other members of this complex, Mycobacterium africanum is the cause of many cases of tuberculosis in West Africa and can be found in other areas mainly in association with immigration. M. bovis BCG is the currently available vaccine for tuberculosis, but it can cause disease in some patients. Other members of the M. tuberculosis complex are mainly animal pathogens with only exceptional cases of human disease, and there are even some strains, like "Mycobacterium canettii," which is a rare human pathogen that could have an important role in the knowledge of the evolution of tuberculosis in the history.
- Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione as anti-mycobacterial agents. [Journal Article]
- CBChem Biol Drug Des 2017 Jan 12
- Resistance among dormant mycobacteria leading to multi-drug resistant (MDR) and extremely-drug resistant(XDR) tuberculosis is one of the major threats. Hence, a series of 1,2,4-triazole-3-thione and ...
Resistance among dormant mycobacteria leading to multi-drug resistant (MDR) and extremely-drug resistant(XDR) tuberculosis is one of the major threats. Hence, a series of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione derivatives (4a-5c) have been synthesised and screened for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). Thetriazolethiones4b and 4v showed high anti-tubercular activity (both MIC and IC50 ) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity towards mycobacteria than other gram-negative and gram-positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/mL against THP-1, A549 and PANC-1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection. This article is protected by copyright. All rights reserved.
- Mycobacterium kansasii Subtype I Is Associated With Clarithromycin Resistance in China. [Journal Article]
- FMFront Microbiol 2016; 7:2097
- Mycobacterium kansasii is the second most common cause of slowly growing non-tuberculous mycobacteria diseases in China. The aim of the present study was to analyze M. kansasii subtypes isolated from...
Mycobacterium kansasii is the second most common cause of slowly growing non-tuberculous mycobacteria diseases in China. The aim of the present study was to analyze M. kansasii subtypes isolated from patients in China, and to explore the antimicrobial susceptibility of the differentiation among these diverse subtypes. A total of 78 M. kansasii strains from 16 provinces of China were enrolled in this study. Amikacin (AMK) was the most highly active against M. kansasii strains, and only 4 isolates (5.1%) exhibited in vitro resistance to AMK. The percentage of levofloxacin (LFX) resistant strains among the 78 M. kansasii isolates was 39.7% (31/78), which was significantly higher than that of moxifloxacin (16.7%, P = 0.001) and gatifloxacin (19.2%, P = 0.005). By using PCR-restriction fragment analysis of the hsp65 gene (PRA), all the isolates were classified as four different subtypes. Of these four subtypes, M. kansasii subtype I was the most frequent genotype in China, accounting for 71.8% (56/78) of M. kansasii isolates. Resistance to clarithromycin (CLA) was noted in 26.8% (15/56) of subtype I isolates, which was significant higher than that of other subtypes (4.5%, P = 0.031). DNA sequencing revealed that the presence of mutations in 23S rRNA was associated with 56.2% (9/16) of CLA-resistant M. kansasii isolates. In conclusion, our data demonstrate that AMK is the most active agent against M. kansasii in vitro, while the high proportion of CLA resistance is noted in M. kansasii isolates. In addition, the predominant subtype I is associated with CLA resistance in China.
New Search Next
- The Bare Essentials of Antibiotic Target Validation. [Journal Article]
- AIACS Infect Dis 2017 Jan 13; 3(1):2-4
- The convergence of competitive fitness experiments and phenotypic screening would seem to be an auspicious beginning for validation of an antibacterial target. IMPDH was already identified an essenti...
The convergence of competitive fitness experiments and phenotypic screening would seem to be an auspicious beginning for validation of an antibacterial target. IMPDH was already identified an essential protein in Mycobacterium tuberculosis when not one, but two, groups discovered inhibitors with promising antitubercular activity. A new target appeared to be born. Surprisingly, the two groups came to completely different conclusions about the vulnerability of IMPDH and its future as a drug target. This viewpoint discusses these papers and how to resolve this conundrum.