Generating a Peptide Library Using the Repeats of Amino Acid Scaffolds Created by Sliding the Framework of a 7-mer Human Chemerin Segment and Discovery of Potent Antibacterial and Antimycobacterial Peptides.

The quest for new approaches for generating novel bioactive designer proteins/peptides has continued with their success in various biomedical applications. Previously, we designed a 14-mer α-helical peptide with antimicrobial and antimycobacterial activities by employing a tandem repeat of the 7-mer, "KVLGRLV" human chemerin segment. Herein, we devised a new method of "sliding framework" with this segment to create amino acid scaffolds of varying sizes and sequences and explored the design of a peptide library with antibacterial and antimycobacterial activities.

Antitubercular evaluation of dihydropyridine-triazole conjugates: design, synthesis, screening, SAR and ADME predictions.

This study investigates the potential of click chemistry for the development of novel anti-tuberculosis agents. A targeted library of 1,4-dihydropyridine-1,2,3-triazole conjugates was synthesized and evaluated for their activity against HRa using the resazurin microtiter assay (REMA). Among the synthesized derivatives, compounds J10, J11, J14, J22 and J23 demonstrated significant antimycobacterial activity.

Tandem Repeat of a Short Human Chemerin-Derived Peptide and Its Nontoxic d-Lysine-Containing Enantiomer Display Broad-Spectrum Antimicrobial and Antitubercular Activities.

To design novel antimicrobial peptides by utilizing the sequence of the human host defense protein, chemerin, a seven-residue amphipathic stretch located in the amino acid region, 109-115, was identified, which possesses the highest density of hydrophobic and positively charged residues. Although this 7-mer peptide was inactive toward microorganisms, its 14-mer tandem repeat (Chem-KVL) was highly active against different bacteria including methicillin-resistant , a multidrug-resistant strain, and slow- and fast-growing mycobacterial species. The selective enantiomeric substitutions of its two l-lysine residues were attempted to confer cell selectivity and proteolytic stability to Chem-KVL.

Targeting Mycobacterium Tuberculosis Enoyl-Acyl Carrier Protein Reductase Using Computational Tools for Identification of Potential Inhibitor and their Biological Activity.

Enoyl-acyl carrier protein reductase (InhA) of type II fatty acid synthase system is involved in the synthesis of mycolic acids which is a major component of the bacterial cell wall. Since they are the key enzymes playing a very significant role in the FASII pathway of the bacterium. In this study, we have developed a workflow for identification of InhA inhibitors by utilizing in silico virtual screening approaches based on various machine learning algorithms followed by pharmacophore based virtual screening.

Synthesis of 2-methoxy-3-(thiophen-2-ylmethyl)quinoline containing amino carbinols as antitubercular agents.

We have designed and synthesized 2-methoxy-3-(thiophen-2-ylmethyl)quinoline containing amino carbinols as possible anti-tubercular agents to combat the disease. These molecules were synthesized by tethering amino ether linkage with hydroxyl group to diarylquinoline skeleton; hydroxyl and amine chains were engrafted on diaryl ring. They were evaluated against strain (HR) of Mycobacterium tuberculosis and most of compounds showed in vitro antitubercular activity.

Catalase Expression in Azospirillum brasilense Sp7 Is Regulated by a Network Consisting of OxyR and Two RpoH Paralogs and Including an RpoE1→RpoH5 Regulatory Cascade.

The genome of encodes five RpoH sigma factors: two OxyR transcription regulators and three catalases. The aim of this study was to understand the role they play during oxidative stress and their regulatory interconnection. Out of the 5 paralogs of RpoH present in , inactivation of only renders heat sensitive.

hsa-let-7b-5p facilitates Mycobacterium tuberculosis survival in THP-1 human macrophages by Fas downregulation.

Tuberculosis continues to be one of the deadliest infectious diseases worldwide. MicroRNAs (miRNAs) are small non-coding entities that play critical role as post-transcriptional regulators and are transcriptionally deregulated upon mycobacterial infection. In this study, we found significant upregulation of hsa-let-7b-5p in Mycobacterium tuberculosis (MTB) infected THP-1 human macrophages.

Regulation of a Glycerol-Induced Quinoprotein Alcohol Dehydrogenase by σ and a LuxR-Type Regulator in Azospirillum brasilense Sp7.

Sp7 uses glycerol as a carbon source for growth and nitrogen fixation. When grown in medium containing glycerol as a source of carbon, it upregulates the expression of a protein which was identified as quinoprotein alcohol dehydrogenase (ExaA). Inactivation of adversely affects the growth of on glycerol.

Carotenoid Biosynthetic Pathways Are Regulated by a Network of Multiple Cascades of Alternative Sigma Factors in Azospirillum brasilense Sp7.

Unlabelled: Carotenoids constitute an important component of the defense system against photooxidative stress in bacteria. In Azospirillum brasilense Sp7, a nonphotosynthetic rhizobacterium, carotenoid synthesis is controlled by a pair of extracytoplasmic function sigma factors (RpoEs) and their cognate zinc-binding anti-sigma factors (ChrRs). Its genome harbors two copies of the gene encoding geranylgeranyl pyrophosphate synthase (CrtE), the first critical step in the carotenoid biosynthetic pathway in bacteria.

Characterization of Mycobacterium smegmatis sigF mutant and its regulon: overexpression of SigF antagonist (MSMEG_1803) in M. smegmatis mimics sigF mutant phenotype, loss of pigmentation, and sensitivity to oxidative stress.

In Mycobacterium smegmatis, sigF is widely expressed during different growth stages and plays role in adaptation to stationary phase and oxidative stress. Using a sigF deletion mutant of M. smegmatis mc(2) 155, we demonstrate that SigF is not essential for growth of bacterium.

Double recombinant Mycobacterium bovis BCG strain for screening of primary and rationale-based antimycobacterial compounds.

Conventional antimycobacterial screening involves CFU analysis, which poses a great challenge due to slow growth of mycobacteria. Recombinant strains carrying reporter genes under the influence of constitutive promoters allow rapid and wide screening of compounds but without revealing their modes of action. Reporter strains using pathway-specific promoters provide a better alternative but allow a limited screening of compounds interfering with only a particular metabolic pathway.

Identification and characterization of Rv0494: a fatty acid-responsive protein of the GntR/FadR family from Mycobacterium tuberculosis.

Escherichia coli FadR, a member of the GntR family of transcription factors, plays dual roles in fatty acid metabolism. FadR-DNA binding is inhibited by fatty acyl-CoAs, and thus FadR acts as a sensor of the fatty acid level in bacteria. We have identified FadR-binding sites in the upstream regions of genes showing altered expression after the disruption of fatty acid biosynthesis in Mycobacterium tuberculosis.

Human beta casein fragment (54-59) modulates M. bovis BCG survival and basic transcription factor 3 (BTF3) expression in THP-1 cell line.

Immunostimulatory peptides potentiate the immune system of the host and are being used as a viable adjunct to established therapeutic modalities in treatment of cancer and microbial infections. Several peptides derived from milk protein have been reported to induce immunostimulatory activity. Human β -casein fragment (54-59), natural sequence peptide (NS) carrying the Val-Glu-Pro-Ile-Pro-Tyr amino acid residues, was reported to activate the macrophages and impart potent immunostimulatory activity.

Synthesis and bio-evaluation of alkylaminoaryl phenyl cyclopropyl methanones as antitubercular and antimalarial agents.

A series of 4-alkylaminoaryl phenyl cyclopropyl methanones (6a-6u and 8a-8c) were synthesized from 4-fluorochalcones (3a and 3b) by cyclopropanation of double bond followed by nucleophilic substitution of F with different amines. The compounds were screened for their antitubercular and antimalarial activities against Mycobacterium tuberculosis H37Rv and Plasmodium falciparum 3D7 strains in vitro respectively. Several compounds (6a, 6d-6h, 6p, 6q and 8a-8c) exhibited good in vitro antitubercular activities with MIC values 3.

Differential expression of sigH paralogs during growth and under different stress conditions in Mycobacterium smegmatis.

SigH regulates a transcriptional network that responds to heat and oxidative stress in mycobacteria. Seven sigH paralogs are reported to exist in the Mycobacterium smegmatis genome. A comprehensive real-time reverse transcriptase PCR analysis during different stages of growth and upon exposure to various stress conditions and antimycobacterial compounds showed differential expression of sigH paralogs during stationary phase and severalfold increases in the levels of transcription of sigH1, sigH4, sigH5, sigH6, and sigH7 under specific stress conditions.

Conservation of sigma F in mycobacteria and its expression in Mycobacterium smegmatis.

Alternate sigma factor SigF controls the expression of virulence-associated genes and is believed to contribute to the pathology of tuberculosis. It was reported to be absent in fast-growing nontuberculous mycobacteria until its orthologs were reported recently in a database. In this study, we demonstrate the presence of sigF gene in few commonly studied nonpathogenic mycobacterial species.

A mouse gene encoding a novel member of the WD family of proteins is highly conserved and predominantly expressed in the testis (Wdr13).

Wdr13, a novel member of the WD family of proteins and the mouse homolog of WDR13 is localized to the locus XA1.1 and is predominantly expressed in the testis. The expression begins at the early stages of gonadal development and is maintained throughout the adult life with a predominant expression in the germ cells of adult testis.

A highly conserved human gene encoding a novel member of WD-repeat family of proteins (WDR13).

We have identified and characterized a novel member of the WD-repeat motif gene family, WDR13, which contains 9 exons and 8 introns. The gene has been mapped to the genomic locus Xp11.23 by fluorescent in situ hybridization and in silico mapping.