Genes and regulatory networks involved in persistence of Mycobacterium tuberculosis

The causative agent of tuberculosis,Mycobacterium tuberculosis,is one of the most successful of human pathogens.It can evade the host immune response and establish a persistent infection or enter a dormant state within the host which can be reactivated if the host becomes immuno-compromised.Both of these features are major obstacles to tuberculosis eradication.Dormancy and reactivation of M.tuberculosis are tightly coordinated dynamic processes involving numerous genes and their products.Molecular mechanisms underlying M.tuberculosis persistence may provide an opportunity for the discovery of effective drug targets for tuberculosis control.Here,we review the genes required for M.tuberculosis persistence and propose a regulatory network for the action of these genes using text mining.This should provide fresh insights into the persistence mechanisms of M.tuberculosis and suggest candidates for new drug targets and immune intervention.

Type I interferon： the mediator of bacterial infection-induced necroptosis

COMMENTARY Innate immune responses are essential for the host to fight against invading microbes. Innate immune receptors or pattern recog- nition receptors recognize conserved microbial molecules and trigger innate immune res- ponses. Pattern recognition receptors such as Toll-like receptors primarily signal through the adaptor MyD88 to activate NF-~B, while other Toll-like receptors signal v/a TRIF to activate IRF-3 resulting in the expression of type I interferons （IFNs）.a Type I IFNs play a crucial role in antiviral immune responses but are also important for the host response against bac- terial infection.2 Paradoxically.

A streamlined high throughput screening method for the Mycobacterium neoaurum mutants with expected yield of biotransformation derivatives from sterols

Steroidal drugs have wide indications such as anti-inflammation, anti-tumor, endocrine regulation,fertility management. Phytosterol is the main starting materials for the industrial synthesis of steroid drugs. Microbial transformation of phytosterol is a simple and environmentally friendly process. Efficient microbial strains for industrial phytosterol transformation are critical for the commercial success. To this end, a 96-well plate based method was developed to discriminate the mixture of 4-androstene-3,17-dione, androsta-1,4-diene-3,17-dione, and bisnoraldehyde, with different ratio of the 3 components in the mixture, which mimics the sterol bioconversion products by using the Mycobacterium neoaurum. The M. neoaurum bioconversed broth test using phytosterol as substrate also found that the spectrum methodology can evaluate the relative content of different compounds. The method is practical, high throughput and can replace the conventional HPLC-based assay for rapid selection of desired microbial strains.

Protein post-translational modification by lysine succinylation:Biochemistry,biological implications,and therapeutic opportunities

Lysine succinylation(Ksuc)is a novel protein post-translational modification(PTM)wherein a succinyl group modifies a lysine residue.Ksuc leads to significant chemical and struc-tural changes to the modified protein.Recent studies have shown that Ksuc might play an important role in organism physiology and some pathophysiological processes,such as tumor-igenesis and metabolic diseases.To provide an understanding of the molecular mechanism and functions of Ksuc in different organisms,we reviewed the current literature about Ksuc,mainly summarizing the research advances in eukaryotes and prokaryotes based on both traditional study methods and site prediction tools.We also discussed inhibitors or activators associated with Ksuc that may contribute to proteomic studies and could be useful in future clinical prac-tice.A deeper understanding of Ksuc may shed new light on life science at the protein level and could lead to novel therapeutic strategies for various diseases.

Antibiotic drugs targeting bacterial RNAs

RNAs have diverse structures that include bulges and internal loops able to form tertiary contacts or serve as ligand binding sites.The recent increase in structural and functional information related to RNAs has put them in the limelight as a drug target for small molecule therapy.In addition,the recognition of the marked difference between prokaryotic and eukaryotic rRNA has led to the development of antibiotics that specifically target bacterial rRNA,reduce protein translation and thereby inhibit bacterial growth.To facilitate the development of new antibiotics targeting RNA,we here review the literature concerning such antibiotics,mRNA,riboswitch and tRNA and the key methodologies used for their screening.

Advances in Mycobacterium siderophore-based drug discovery

Tuberculosis remains a public health threat of global proportions.Iron is a scarce resource indispensable to both host and pathogen during infection with Mycobacterium tuberculosis,the causative agent of tuberculosis.Siderophores are critical molecules for iron acquisition under iron-limiting conditions and,as a very efficient pathogen,M.tuberculosis has evolved elaborate siderophores knowledge of which is being intensively translated into clinical practice.This paper summarizes the structures,types and physiological functions of Mycobacterium siderophores with emphasis on siderophore-inspired design of drugs and drug delivery vehicles.

Exploring Mycobacterium tuberculosis infection-induced alterations in gene expression in macrophage by microarray hybridization

Tuberculosis remains a serious threat to public health. Its causative agent Mycobacte- rium tuberculosis is an intracellular pathogen which survives and replicates within cells of the host immune system, primarily macrophages. Knowledge of the bacteria-macrophage interaction can help to develop novel measures to combat the disease. The global gene expression of macro- phage following invasion by and growth of M. tuberculosis was studied by cDNA microarray. Of the 12800 human genes analyzed, totally 473 (3.7%) macrophage genes were differentially expressed after being infected by M. tuberculosis, among which, only 25 (5.2%, corresponding to less than 0.2% of the 12800 genes) genes were up-regulated, while others (94.8%) were down-regulated against the control. Of the 473 genes, 376 genes are registered in the GenBank, and 97 are novel genes. Expression of 5 up-regulated genes has been induced by more than 3-fold. 25 genes were down-regulated by more than 3-fold. Syndecan binding protein has been down-regu- lated up to 12.5-fold. The data gave an insight into the early gene expression in macrophage ensuing M. tuberculosis infection and a basis for further study.

Transposon-based screen identifies a XRE family regulator crucial for candicidin biosynthesis in Streptomyces albus J1074

Dear Editor,Polyene macrolides are a group of natural products with potent antifungal activity (Caffrey et al., 2016). Candicidin/FR-008, a potent broad-spectrum anti-fungal agent, is produced by several Streptomycetes, including Streptomycetes sp. strain FR-008 (Chen et al., 2003), S. griseus 3570(Campelo and Gil, 2002) and S. albus J1074 (Olano et al.,2014). Due to its medical importance, considerable effort has been applied to elucidate its biosynthetic pathway and identify key regulatory genes (Chen et al., 2003;Zhang et al.,2015).

Mycobacterium Lrp/AsnC family transcriptional factor modulates the arginase pathway as both a sensor and a transcriptional repressor

L-Arginine is the precursor of nitric oxide(NO),a host immune effector against intracellular pathogens including Mycobacterium tuberculosis(M.tb).Pathogens including M.tb have evolved various strategies targeting arginine to block the production of NO for better survival and proliferation.However,L-arginine metabolism and regulation in Mycobacterium are poorly understood.Here,we report the identification of M.smegmatis MSMEG_1415(homolog of M.tb Rv2324)as an arginine-responsive transcriptional factor regulating the arginase pathway.In the absence of L-arginine,MSMEG_1415 acts as a repressor to inhibit the transcription of the roc(for arginine,ornithine catabolism)gene cluster,thereby switching off the arginase pathway.Treatment with L-arginine relieves the transcriptional inhibition of MSMEG_1415 on the roc gene cluster to activate the arginase pathway.Moreover,the L-arginine-MSMEG_1415 complex activates the transcription of the roc gene cluster by recognizing and binding a 15-bp palindrome motif,thereby preventing the excess accumulation of L-arginine in M.smegmatis.Physiologically,MSMEG_1415 confers mycobacteria resistance to starvation and fluoroquinolones exposure,suggestive of its important role in M.smegmatis persistence.The results uncover a unique regulatory mechanism of arginine metabolism in mycobacteria and identify M.tb Rv2324 as an attractive candidate target for the design of drugs against tuberculosis.