- Host-Directed Therapeutics against Mycobacterial Infections. [Journal Article]
- CPCurr Pharm Des 2016 Dec 02
- The high incidence of tuberculosis (TB) in the world, especially in developing countries, the resurgence of TB in industrialized countries, and the global increase in the prevalence of Mycobacterium ...
The high incidence of tuberculosis (TB) in the world, especially in developing countries, the resurgence of TB in industrialized countries, and the global increase in the prevalence of Mycobacterium avium complex infections in immunocompromised hosts have prompted the quest for novel antimycobacterial drugs. However, the development of such antimicrobial chemotherapeutics is currently making very slow progress even with using the bioinformatics-based methodology for drug design. It thus appears that devising improved administration protocols for clinical treatment against intractable mycobacterial infections using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The potentiation of host immune responses using immunoadjunctive agents, alternatively called host-directed therapeutics (HDTs), may increase the efficacy of antimycobacterial regimens against mycobacteriosis. Particularly, the modulation of host immunity relating to macrophage antimicrobial functions may be beneficial to the immunoadjunctive therapy. This review will deal with the current status and future prospects regarding the development of HDTs useful for the clinical control of intractable mycobacterial infections.
- S-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents. [Journal Article]
- EJEur J Med Chem 2016 Nov 21; 126:369-383
- Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relation...
Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 μM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.
- Current trends and intricacies in the management of HIV-associated pulmonary tuberculosis. [Review]
- ARAIDS Res Ther 2016 Sep 26; 13(1):34
- Human immunodeficiency virus (HIV) epidemic has undoubtedly increased the incidence of tuberculosis (TB) globally, posing a formidable global health challenge affecting 1.2 million cases. Pulmonary T...
Human immunodeficiency virus (HIV) epidemic has undoubtedly increased the incidence of tuberculosis (TB) globally, posing a formidable global health challenge affecting 1.2 million cases. Pulmonary TB assumes utmost significance in the programmatic perspective as it is readily transmissible as well as easily diagnosable. HIV complicates every aspect of pulmonary tuberculosis from diagnosis to treatment, demanding a different approach to effectively tackle both the diseases. In order to control these converging epidemics, it is important to diagnose early, initiate appropriate therapy for both infections, prevent transmission and administer preventive therapy. Liquid culture methods and nucleic acid amplification tests for TB confirmation have replaced conventional solid media, enabling quicker and simultaneous detection of mycobacterium and its drug sensitivity profile Unique problems posed by the syndemic include Acquired rifampicin resistance, drug-drug interactions, malabsorption of drugs and immune reconstitution inflammatory syndrome or paradoxical reaction that complicate dual and concomitant therapy. While the antiretroviral therapy armamentarium is constantly reinforced by discovery of newer and safer drugs every year, only a few drugs for anti tuberculosis treatment have successfully emerged. These include bedaquiline, delamanid and pretomanid which have entered phase III B trials and are also available through conditional access national programmes. The current guidelines by WHO to start Antiretroviral therapy irrespective of CD4+ cell count based on benefits cited by recent trials could go a long way in preventing various complications caused by the deadly duo. This review provides a consolidated gist of the advancements, concepts and updates that have emerged in the management of HIV-associated pulmonary TB for maximizing efficacy, offering latest solutions for tackling drug-drug interactions and remedial measures for immune reconstitution inflammatory syndrome.
- Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates. [Journal Article]
- SRSci Rep 2016 Dec 01; 6:38083
- The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an under...
The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents.
- Whole genome sequencing of Mycobacterium tuberculosis provides insight into the evolution and genetic composition of drug-resistant tuberculosis in Belarus. [Journal Article]
- JCJ Clin Microbiol 2016 Nov 30
- The emergence and spread of drug resistant Mycobacterium tuberculosis (DR-TB) is a critical global health issue. Eastern Europe has some of the highest incidences of DR-TB, particularly multidrug-res...
The emergence and spread of drug resistant Mycobacterium tuberculosis (DR-TB) is a critical global health issue. Eastern Europe has some of the highest incidences of DR-TB, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. To better understand the genetic composition and evolution of MDR- and XDR-TB in the region, we sequenced and analyzed the genomes of 138 M. tuberculosis isolates from 97 patients sampled between 2010 and 2013 in Minsk, Belarus. MDR and XDR-TB isolates were significantly more likely to belong to the Beijing lineage than to the Euro-American lineage, and known resistance-conferring loci accounted for the majority of phenotypic resistance to first- and second-line drugs in MDR and XDR-TB. Using a phylogenomic approach, we estimated that the majority of MDR-TB was due to recent transmission of already resistant M. tuberculosis strains rather than repeated de novo evolution of resistance within patients, while XDR-TB was acquired through both routes. Longitudinal sampling of M. tuberculosis from 34 patients with treatment failure showed that most strains persisted genetically unchanged during treatment or acquired resistance to fluoroquinolones. HIV+ patients were significantly more likely to have multiple infections over time than HIV- patients, highlighting a specific need for careful infection control in these patients. These data provide a better understanding of the genomic composition, transmission, and evolution of MDR and XDR-TB in Belarus and will enable improved diagnostics, treatment protocols, and prognostic decision-making.
- True rifampicin resistance missed by the MGIT: prevalence of this pheno/genotype in the UK and Ireland after 18 month surveillance. [Journal Article]
- CMClin Microbiol Infect 2016 Nov 26
- CONCLUSIONS: Rifampicin resistance is missed by the MGIT system. In the UK and Ireland the prevalence of these strains is low. The introduction of routine molecular testing would detect false susceptibility. Further research is needed to ascertain the role of these strains in clinical failure and their prevalence in other settings.
- A Comparison of the Sensititre MycoTB Plate, the Bactec MGIT 960, and a Microarray-Based Molecular Assay for the Detection of Drug Resistance in Clinical Mycobacterium tuberculosis Isolates in Moscow, Russia. [Journal Article]
- PlosPLoS One 2016; 11(11):e0167093
- CONCLUSIONS: The quantitative measures of phenotypic drug resistance produced by the Sensititre MycoTB and the timely detection of mutations using the TB-TEST assay provide guidance for clinicians for the choice of the appropriate drug regimen.
- Division of labor among Mycobacterium smegmatis RNase H enzymes: RNase H1 activity of RnhA or RnhC is essential for growth whereas RnhB and RnhA guard against killing by hydrogen peroxide in stationary phase. [Journal Article]
- NANucleic Acids Res 2016 Nov 28
- RNase H enzymes sense the presence of ribonucleotides in the genome and initiate their removal by incising the ribonucleotide-containing strand of an RNA:DNA hybrid. Mycobacterium smegmatis encodes f...
RNase H enzymes sense the presence of ribonucleotides in the genome and initiate their removal by incising the ribonucleotide-containing strand of an RNA:DNA hybrid. Mycobacterium smegmatis encodes four RNase H enzymes: RnhA, RnhB, RnhC and RnhD. Here, we interrogate the biochemical activity and nucleic acid substrate specificity of RnhA. We report that RnhA (like RnhC characterized previously) is an RNase H1-type magnesium-dependent endonuclease with stringent specificity for RNA:DNA hybrid duplexes. Whereas RnhA does not incise an embedded mono-ribonucleotide, it can efficiently cleave within tracts of four or more ribonucleotides in duplex DNA. We gained genetic insights to the division of labor among mycobacterial RNases H by deleting the rnhA, rnhB, rnhC and rnhD genes, individually and in various combinations. The salient conclusions are that: (i) RNase H1 activity is essential for mycobacterial growth and can be provided by either RnhC or RnhA; (ii) the RNase H2 enzymes RnhB and RnhD are dispensable for growth and (iii) RnhB and RnhA collaborate to protect M. smegmatis against oxidative damage in stationary phase. Our findings highlight RnhC, the sole RNase H1 in pathogenic mycobacteria, as a candidate drug discovery target for tuberculosis and leprosy.
- Cytosolic Proteome Profiling of Aminoglycosides Resistant Mycobacterium tuberculosis Clinical Isolates Using MALDI-TOF/MS. [Journal Article]
- FMFront Microbiol 2016; 7:1816
- Emergence of extensively drug resistant tuberculosis (XDR-TB) is the consequence of the failure of second line TB treatment. Aminoglycosides are the important second line anti-TB drugs used to treat ...
Emergence of extensively drug resistant tuberculosis (XDR-TB) is the consequence of the failure of second line TB treatment. Aminoglycosides are the important second line anti-TB drugs used to treat the multi drug resistant tuberculosis (MDR-TB). Main known mechanism of action of aminoglycosides is to inhibit the protein synthesis by inhibiting the normal functioning of ribosome. Primary target of aminoglycosides are the ribosomal RNA and its associated proteins. Various mechanisms have been proposed for aminoglycosides resistance but still some are unsolved. As proteins are involved in most of the biological processes, these act as a potential diagnostic markers and drug targets. In the present study we analyzed the purely cytosolic proteome of amikacin (AK) and kanamycin (KM) resistant Mycobacterium tuberculosis isolates by proteomic and bioinformatic approaches. Twenty protein spots were found to have over expressed in resistant isolates and were identified. Among these Rv3208A, Rv2623, Rv1360, Rv2140c, Rv1636, and Rv2185c are six proteins with unknown functions or undefined role. Docking results showed that AK and KM binds to the conserved domain (DUF, USP-A, Luciferase, PEBP and Polyketidecyclase/dehydrase domain) of these hypothetical proteins and over expression of these proteins might neutralize/modulate the effect of drug molecules. TBPred and GPS-PUP predicted cytoplasmic nature and potential pupylation sites within these identified proteins, respectively. String analysis also suggested that over expressed proteins along with their interactive partners might be involved in aminoglycosides resistance. Cumulative effect of these over expressed proteins could be involved in AK and KM resistance by mitigating the toxicity, repression of drug target and neutralizing affect. These findings need further exploitation for the expansion of newer therapeutics or diagnostic markers against AK and KM resistance so that an extreme condition like XDR-TB can be prevented.
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- Molecular investigation of resistance to second line injectable drugs in multidrug-resistant clinical isolates of Mycobacterium tuberculosis in France. [Journal Article]
- AAAntimicrob Agents Chemother 2016 Nov 28
- The second line injectable drugs (SLID, i.e. amikacin, kanamycin, capreomycin) are key drugs for the treatment of multidrug-resistant tuberculosis. Mutations in rrs region 1400, tlyA and eis promoter...
The second line injectable drugs (SLID, i.e. amikacin, kanamycin, capreomycin) are key drugs for the treatment of multidrug-resistant tuberculosis. Mutations in rrs region 1400, tlyA and eis promoter are associated with resistance to SLID, to capreomycin and to kanamycin respectively. In this study, the sequencing data of SLID resistance-associated genes were compared to the results of phenotypic drug susceptibility testing by the proportion method for the SLID in 206 multidrug-resistant clinical isolates of Mycobacterium tuberculosis collected in France. Among the 153 isolates susceptible to the 3 SLID, 145 showed no mutation, 1 harbored T1404C plus G1473A mutations in rrs and 7 had an eis promoter mutation. Among the 53 strains resistant to at least 1 of the SLID, mutations in rrs accounted for resistance to amikacin, capreomycin and kanamycin for 81%, 75% and 44% isolates, respectively, while mutations in eis promoter were detected in 44% of the isolates resistant to kanamycin. By contrast, no mutations in tlyA were observed in the isolates resistant to capreomycin. The discrepancies observed between the genotypic (on the primary culture) and phenotypic drug susceptibility testing were explained by i) resistance to SLID with MICs close to the critical concentration used for routine DST and not detected by phenotypic testing (n=8, 15% of SLID-resistant strains), ii) low-frequency heteroresistance not detected by sequencing of drug resistance-associated genes on the primary culture (n=8, 15% of SLID-resistant strains), and iii) to other resistance mechanisms not yet characterized (n=7, 13% of SLID-resistant strains).