scholarly journals Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets

Pathogens ◽  
2018 ◽  
Vol 7 (1) ◽  
pp. 17 ◽  
Author(s):  
◽  
◽  
◽  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Survival Strategies ◽  
World Population ◽  
Antitubercular Agents ◽  
Antitubercular Drugs ◽  
Major Threat ◽  
Lung Tuberculosis ◽  
Molecular Determinants ◽  
Effective Shield ◽  
Prevalent Form

Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate the compliance and monitoring of drug administration and treatment. Moreover, the only available antitubercular vaccine fails to provide an effective shield against adult lung tuberculosis, which is the most prevalent form. Hence, there is a pressing need for effective antitubercular drugs and vaccines. This review highlights recent advances in the study of selected M. tuberculosis key molecular determinants of infection and vulnerable targets whose structures could be exploited for the development of new antitubercular agents.

scholarly journals Selective Mycobacterium tuberculosis Shikimate Kinase Inhibitors as Potential Antibacterials

2015 ◽  
Vol 7 ◽  
pp. PMC.S13212 ◽  
Author(s):  
Sara Gordon ◽  
Johayra Simithy ◽  
Douglas C. Goodwin ◽  
Angela I. Calderón
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Kinase Inhibitors ◽  
Shikimate Pathway ◽  
Multidrug Resistant ◽  
Antitubercular Agents ◽  
Shikimate Kinase ◽  
Antitubercular Drugs ◽  
Inhibitor Discovery

Owing to the persistence of tuberculosis (TB) as well as the emergence of multidrug-resistant and extensively drug-resistant (XDR) forms of the disease, the development of new antitubercular drugs is crucial. Developing inhibitors of shikimate kinase (SK) in the shikimate pathway will provide a selective target for antitubercular agents. Many studies have used in silico technology to identify compounds that are anticipated to interact with and inhibit SK. To a much more limited extent, SK inhibition has been evaluated by in vitro methods with purified enzyme. Currently, there are no data on in vivo activity of Mycobacterium tuberculosis shikimate kinase ( MtSK) inhibitors available in the literature. In this review, we present a summary of the progress of SK inhibitor discovery and evaluation with particular attention toward development of new antitubercular agents.

The crystal structure of an essential high-temperature requirement protein HtrA1 (Rv1223) from Mycobacterium tuberculosis reveals its unique features

2018 ◽  
Vol 74 (9) ◽  
pp. 906-921 ◽  
Author(s):  
Khundrakpam Herojit Singh ◽  
Savita Yadav ◽  
Deepak Kumar ◽  
Bichitra Kumar Biswal
Keyword(s):  
Crystal Structure ◽  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
High Temperature ◽  
Protein Quality ◽  
Pdz Domain ◽  
Survival Strategies ◽  
Dimensional Structure ◽  
Protease Domain ◽  
Temperature Requirement

High-temperature requirement A (HtrA) proteins, which are members of the heat-shock-induced serine protease family, are involved in extracytoplasmic protein quality control and bacterial survival strategies under stress conditions, and are associated with the virulence of several pathogens; they are therefore major drug targets. Mycobacterium tuberculosis possesses three putative HtrAs: HtrA1 (Rv1223), HtrA2 (Rv0983) and HtrA3 (Rv0125). Each has a cytoplasmic region, a transmembrane helix and a periplasmic region. Here, the crystal structure of the periplasmic region consisting of a protease domain (PD) and a PDZ domain from an M. tuberculosis HtrA1 mutant (mHtrA1S387A) is reported at 2.7 Å resolution. Although the mHtrA1S387A PD shows structural features similar to those of other HtrAs, its loops, particularly L3 and LA, display different conformations. Loop L3 communicates between the PDs of the trimer and the PDZ domains and undergoes a transition from an active to an inactive conformation, as reported for an equivalent HtrA (DegS). Loop LA, which is responsible for higher oligomer formation owing to its length (50 amino acids) in DegP, is very short in mHtrA1S387A (five amino acids), as in mHtrA2 (also five amino acids), and therefore lacks essential interactions for the formation of higher oligomers. Notably, a well ordered loop known as the insertion clamp in the PDZ domain interacts with the protease domain of the adjacent molecule, which possibly aids in the stabilization of a trimeric functional unit of this enzyme. The three-dimensional structure of mHtrA1S387A presented here will be useful in the design of enzyme-specific antituberculosis inhibitors.

scholarly journals Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1205 ◽  
Author(s):  
Riccardo Miggiano ◽  
Castrese Morrone ◽  
Franca Rossi ◽  
Menico Rizzi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Genome Stability ◽  
Current Knowledge ◽  
Genome Integrity ◽  
Dna Integrity ◽  
Dna Metabolism ◽  
Nucleotide Synthesis ◽  
Antitubercular Drugs ◽  
Molecular Events

Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent anti-tubercular regimens can lead to the anticipated non-compliance of the patient and increased drug toxicity, which in turn can contribute to the emergence of drug-resistant MTB strains that are not susceptible to first- and second-line available drugs. Hence, there is an urgent need for innovative antitubercular drugs and vaccines. A number of biochemical processes are required to maintain the correct homeostasis of DNA metabolism in all organisms. Here we focused on reviewing our current knowledge and understanding of biochemical and structural aspects of relevance for drug discovery, for some such processes in MTB, and particularly DNA synthesis, synthesis of its nucleotide precursors, and processes that guarantee DNA integrity and genome stability. Overall, the area of drug discovery in DNA metabolism appears very much alive, rich of investigations and promising with respect to new antitubercular drug candidates. However, the complexity of molecular events that occur in DNA metabolic processes requires an accurate characterization of mechanistic details in order to avoid major flaws, and therefore the failure, of drug discovery approaches targeting genome integrity.

scholarly journals Synthesis and Preliminary Evaluation of Benzofuran-Oxadiazole Conjugates as Potential Antitubercular Agents

2019 ◽  
Vol 31 (4) ◽  
pp. 965-970 ◽  
Author(s):  
Veerabhadrayya S. Negalurmath ◽  
Obelannavar Kotresh ◽  
Mahantesha Basanagouda
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Spectral Data ◽  
13C Nmr ◽  
Antitubercular Activity ◽  
Preliminary Evaluation ◽  
Antitubercular Agents ◽  
Mass Spectral Data ◽  
Mass Spectral ◽  
Mycobacterium Tuberculosis H37rv ◽  
Mycobacterium Phlei

In the present study, a series of benzofuran-oxadiazole conjugates 7(a-o) was designed, synthesized and characterized through IR, 1H NMR, 13C NMR and mass spectral data. All the compounds were screened for preliminary antitubercular activity against Mycobacterium phlei and Mycobacterium tuberculosis H37RV. Among all the target compounds, the compound possessing chlorine (7k, MIC 1.56 μg/mL) and bromine (7m, MIC 1.56 μg/mL) on 6th position of benzofuran showed highest activity against Mycobacterium phlei. Whereas, bromine on either 5th position (7l, MIC 3.125 μg/mL) or 6th position (7m MIC 3.125 μg/mL) on benzofuran exhibited highest activity for Mycobacterium tuberculosis (H37 RV).

Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis

2016 ◽  
Vol 59 (6) ◽  
pp. 2362-2380 ◽  
Author(s):  
Galina Karabanovich ◽  
Júlia Zemanová ◽  
Tomáš Smutný ◽  
Rita Székely ◽  
Michal Šarkan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antitubercular Agents

RD7 genotyping of Mycobacterium tuberculosis strains isolated from patients with lung tuberculosis in various areas of Kazakhstan

2008 ◽  
Vol 23 (2) ◽  
pp. 71-76
Author(s):  
V. V. Demkin ◽  
I. N. Korneva ◽  
Yu. A. Ryazanova ◽  
T. A. Muminov ◽  
Sh. A. Beisembayeva ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Lung Tuberculosis

Design, synthesis and evaluation of diphenyl ether analogues as antitubercular agents

RSC Advances ◽  
2016 ◽  
Vol 6 (112) ◽  
pp. 110571-110582 ◽  
Author(s):  
Bharathkumar Inturi ◽  
Gurubasavaraj V. Pujar ◽  
Madhusudhan N. Purohit ◽  
Viswanathan B. Iyer ◽  
Sowmya G. S. ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Acyl Carrier Protein ◽  
Diphenyl Ether ◽  
Design Approach ◽  
Carrier Protein ◽  
Antitubercular Agents ◽  
Structure Based Drug Design ◽  
Design Synthesis ◽  
Diphenyl Ethers

We herein report the investigation of new diphenyl ethers asMycobacterium tuberculosisenoyl-acyl carrier protein reductase (InhA) inhibitors by structure-based drug design approach.

scholarly journals Requirement of the mymA Operon for Appropriate Cell Wall Ultrastructure and Persistence of Mycobacterium tuberculosis in the Spleens of Guinea Pigs

2005 ◽  
Vol 187 (12) ◽  
pp. 4173-4186 ◽  
Author(s):  
Amit Singh ◽  
Radhika Gupta ◽  
R. A. Vishwakarma ◽  
P. R. Narayanan ◽  
C. N. Paramasivan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Parental Strain ◽  
Guinea Pigs ◽  
Cell Envelope ◽  
Sodium Dodecyl ◽  
Phenotypic Traits ◽  
Antitubercular Drugs ◽  
Mycolic Acids ◽  
Increased Sensitivity

ABSTRACT We had recently reported that the mymA operon (Rv3083 to Rv3089) of Mycobacterium tuberculosis is regulated by AraC/XylS transcriptional regulator VirS (Rv3082c) and is important for the cell envelope of M. tuberculosis. In this study, we further show that a virS mutant (MtbΔvirS) and a mymA mutant (Mtbmym::hyg) of M. tuberculosis exhibit reduced contents and altered composition of mycolic acids along with the accumulation of saturated C24 and C26 fatty acids compared to the parental strain. These mutants were markedly more susceptible to major antitubercular drugs at acidic pH and also showed increased sensitivity to detergent (sodium dodecyl sulfate) and to acidic stress than the parental strain. We show that disruption of virS and mymA genes impairs the ability of M. tuberculosis to survive in activated macrophages, but not in resting macrophages, suggesting the importance of the mymA operon in protecting the bacterium against harsher conditions. Infection of guinea pigs with MtbΔvirS, Mtbmym::hyg, and the parental strain resulted in an ∼800-fold-reduced bacillary load of the mutant strains compared with the parental strain in spleens, but not in the lungs, of animals at 20 weeks postinfection. Phenotypic traits were fully complemented upon reintroduction of the virS gene into MtbΔvirS. These observations show the important role of the mymA operon in the pathogenesis of M. tuberculosis at later stages of the disease.

scholarly journals Mycobacterium tuberculosis Lsr2 Is a Global Transcriptional Regulator Required for Adaptation to Changing Oxygen Levels and Virulence

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
I. L. Bartek ◽  
L. K. Woolhiser ◽  
A. D. Baughn ◽  
R. J. Basaraba ◽  
W. R. Jacobs ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
Oxygen Tension ◽  
Reactive Oxygen ◽  
Transcriptional Regulator ◽  
Oxygen Availability ◽  
World Population ◽  
Lung Pathology ◽  
Content Type ◽  
Oxygen Levels

ABSTRACTTo survive a dynamic host environment,Mycobacterium tuberculosismust endure a series of challenges, from reactive oxygen and nitrogen stress to drastic shifts in oxygen availability. The mycobacterial Lsr2 protein has been implicated in reactive oxygen defense via direct protection of DNA. To examine the role of Lsr2 in pathogenesis and physiology ofM. tuberculosis, we generated a strain deleted forlsr2. Analysis of theM. tuberculosisΔlsr2strain demonstrated that Lsr2 is not required for DNA protection, as this strain was equally susceptible as the wild type to DNA-damaging agents. Thelsr2mutant did display severe growth defects under normoxic and hyperoxic conditions, but it was not required for growth under low-oxygen conditions. However, it was also required for adaptation to anaerobiosis. The defect in anaerobic adaptation led to a marked decrease in viability during anaerobiosis, as well as a lag in recovery from it. Gene expression profiling of the Δlsr2mutant under aerobic and anaerobic conditions in conjunction with published DNA binding-site data indicates that Lsr2 is a global transcriptional regulator controlling adaptation to changing oxygen levels. The Δlsr2strain was capable of establishing an early infection in the BALB/c mouse model; however, it was severely defective in persisting in the lungs and caused no discernible lung pathology. These findings demonstrateM. tuberculosisLsr2 is a global transcriptional regulator required for control of genes involved in adaptation to extremes in oxygen availability and is required for persistent infection.IMPORTANCEM. tuberculosiscauses nearly two million deaths per year and infects nearly one-third of the world population. The success of this aerobic pathogen is due in part to its ability to successfully adapt to constantly changing oxygen availability throughout the infectious cycle, from the high oxygen tension during aerosol transmission to anaerobiosis within necrotic lesions. An understanding of howM. tuberculosiscopes with these changes in oxygen tension is critical for its eventual eradication. Using a mutation inlsr2, we demonstrate that the Lsr2 protein present in all mycobacteria is a global transcriptional regulator in control of genes required for adaptation to changes in oxygen levels.M. tuberculosislackinglsr2was unable to adapt to both high and very low levels of oxygen and was defective in long-term anaerobic survival. Lsr2 was also required for disease pathology and for chronic infection in a mouse model of TB.

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