Tianyu Zhang’s Laboratory

                                            Homepage:  http://www.scholat.com/team/ztygroup

Personal Statement：

Since 2002, my research has focused on microbiology, especially on actinomyces

I was recruited to GIBH after completing my fellowship at Johns Hopkins University in September, 2010. My research focuses on physiology of Mtb with a focus on developing new drugs against TB. Tens of chemistry groups all over the world come to collaborate with my lab. We have had very good collaboration with all of them. One good example is that we have co-developed an antituberculosis drug candidate, TB47, and sold it to a company in Dec 2015. My lab was responsible for the biological part including the in vitro activity testing against drug-resistant clinical isolates and the in vivo study using virulent Mtb infected mouse model in ABSL-3 lab. We also had cooperative project about antimycobacterial drug discovery with CSIRO (Australia) supported by CAS and CSIRO. We verified the Cys154Arg mutation in the ribosomal protein L3 can cause resistance to oxazolidinone. We found a potential new target of the first-line anti-TB drug pyrazinamide and explained from a new way about the persisters in 2017. We also found mutation ethAW21R Confers Co-resistance to Protionamide and Ethionamide in both M. bovis BCG and M. tuberculosis H37Rv. We have identified several gene mutations which can confer resistance to two new antituberculosis compounds discovered by us very recently using genome sequencing and genetic verification (unpublished). A compound COMX showed super powerful activity against M. ulcerans infection, which might shorten the duration from more than two months to ~five days. At least four series of compounds from four of our long-term partners showed antituberculosis activity in vivo very recently. We also created selectable marker-free M. abscess using a new system. All these are unpublished.

I started my collaboration with Guangzhou Chest Hospital from early 2011. And then we established the Tuberculosis Lab of State Key Laboratory of Respiratory Disease in Feb 2012 and I am the co-director of the lab since then. In 2014, we reported the finding that 3’ end of rpsA might be added as the target of molecular detection of pyrazinamide susceptibility. These are typical results of my collaboration with clinical experts and doctors to solve some clinical problems. Until now, we have co-published more than 10 papers. In addition, we have got 5 funds together.

So much of my work has involved studying the gene, genome, testing activity of drugs against Mtb/M. ulcerans both in vitro and in vivo. Along with my past and ongoing collaborations with many experts, the knowledge and expertise gained from above experiences will translate readily to my proposed role as PI in China part.

Education/Training：

Positions and Honors：

Research area:

Dr. Zhang’s researches mainly focus on the postgenomics of Mycobacterium tuberculosis; Immunology and the research & development of vaccine of tuberculosis; The research & development of anti-tuberculosis drugs and diagnostic tools and the study of mechanism of the drug action and drug resistance; the research & development of anti gram-negative pathogenic bacteria (such as Helicobacter pylori, Klebsiella pneumoniae) drugs and their mechanisms of action.

Contribution to Science：

1. Established Validated Murine Model of LTBI Chemotherapy and Developed Pharmacodynamics-based Rationale and Experimental Evidence Base for  New LTBI Treatment.

I refined a mouse model of latent tuberculosis (TB) to increase its predictive value and using it to demonstrate the promise of daily rifapentine-containing regimens for ultra-short treatment of latent TB infection and TMC207(bedaquiline)-containing regimens for potential  treatment of latent MDR-TB infection. The results demonstrated that the high-dose daily rifapentine may shorten the treatment duration for latent TB infection (LTBI), leading directly to the NIH ACTG 5279 trial (NCT01404312) comparing 1 month of rifapentine-INH to 9 months of INH. In addition, TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months. The series of work were carried out mainly by me in Eric Nuermberger’s Lab.

2. Established Rapid, Economic High-throughput Screening and Evaluation Anti-antimycobacterial Compounds Platform.

I constructed autoluminescent M. tuberculosis and M. ulcerans strains respectively, and found they were useful in both in vitro high-throughput screening and evaluation of compounds against them in vivo in live mice in labs of Eric Nuermberger, Jacques Grosset and William Bishai. Use of these autoluminescent reporter strains has the potential to drastically reduce the time, effort, animals and costs consumed in the evaluation of drug activity in vitro and the in vivo assessment of drug and even vaccine efficacy. Furthermore, Tianyu Zhang’s lab developed an improved system (authorized patent: ZL 201310386264.0) for efficient construction of unmarked recombinant mycobacteria and constructed the new generation of selection-marker free autoluminescent M. smegmatis, M. tuberculosis, M. marinum and M. bovis BCG strains (authorized patent ZL 201210183007.2). We also engineered selection-marker free autoluminescent M.abscessus using a new selection marker and a new delivery system (submitted, patent 201510104936.3). Now we have established the whole platform for high-throughput screening and evaluation anti-antimycobacterial compounds. It mainly depends on the autoluminescent mycobacteria which need not adding substrates and it is useful at 3 different levels: in vitro, in macrophage and in mice (even in live mice). This platform was reported by tens of media in China.

3. Development of Antimycobacterial Agents.

Shortly after I joined GIBH, I started to establish broad relationships with chemists both in and out of China. More than 30 laboratories have put their compounds/mixture to my lab for screening/evaluation. We also bought some special compound library for antituberculosis drug discovery. Until now we have screened >45,000 compounds and filed Chinese patents for 4 series of compounds and 1 PCT (CN2015/086852). The latter one (for new candidate TB47) has been transferred to Eggbio, a Chinese company, for 20 Million RMB+2% sale. TB47showed very good activity both in vitro (MIC=0.003μg/mL) and in vivo and very low toxicity. We are accelerating it into clinical study. We collaborated with CSIRO Flagship and got the fund for CAS-CSIRO cooperative project to co-develop antimycobacterial drugs. Recently, we found some potent new anti-TB compounds. As mentioned above, At least four series of compounds from four different long-term partners showed antituberculosis activity in vivo very recently. My own group has synthesized many PZA derivatives and discovered one showing very good activity in vivo.

4. Mechanisms of Action of Antimycobacterial Drugs and New Compounds.

Many mycobacteria are resistant to many common antibiotics and so very few marker genes (only 2) can be used in them. Tianyu Zhang’s lab developed improved new system for constructing selection-marker free mycobacteria as mentioned above and so the marker genes can be reused in them. This system is useful in genetic study of mycobacteria. In addition, we have mastered skills for mycobacterial genetic manipulation, such as using the high efficient transposon tool, identification of the insertion site, gene knock-out, overexpression, to study the mechanism of antimycobacterial compounds. Sulfonamides, for example sulfamethoxazole (SMX), have been widely used for treatment of bacterial infection. However, they were not used for tuberculosis. Recently, some studies showed that SMX is active against many clinical M. tuberculosis isolates. The target of  SMX was dihydropteroate synthase (DHPS, FolP) encoded by folp gene in many bacteria. However, there are two folp genes, folp1 and folp2.  In our study we found that Folp1 is the target and Folp2 is a protein that can inhibit the activity of SMX. So a Folp2 inhibitor may act synergistically with SMX to increase its activity against M. tuberculosis. We collaborated with Gyanu Lamichhane et al to study the mechanism of oxazolidinones and confirmed that the mutation of rplC (T460C) was the dominant mutation causing resistance of oxazolidinones. We have found Rv2783 as a potential new target of the first-line drug, pyrazinamide. Now we have found 2 series of compounds may have new targets (still going on) by sequencing the genes/genomes of the resistant mutants.

5.Found 3’ end of rpsA as the second molecular marker for detection of pyrazinamide susceptibility.

In 2012, my lab and Guangzhou Chest Hospital, the biggest tuberculosis treatment center located in southern China, established Tuberculosis Lab of State Key Laboratory of Respiratory Disease. After that, I collaborated with clinical doctors and technicians to solve some clinical problems. We sequenced pncA and rpsA genes plus flanking regions of 161 M. tuberculosis isolates and found 10 new pncA and 3 novel rpsA mutations in pyrazinamide-resistant strains. The 3’ end of rpsA might be added as the target of molecular detection of pyrazinamide susceptibility. Later, we have got several funds together for other studies supported by the Guangzhou Science Technology and Innovation Commission and NSFC etc.

Personnel:

Publications:

1. First or corresponding author article

[1] Zhang N, Liu Z, Liang J, Tang Y, Qian Lu, Gao Y, Zhang T*, Ming Yan*. Design, synthesis, and biological evaluation of m-amido phenol derivatives as a new class of antitubercular agents. Med Chem Comm (Accepted).

[2] Liu P, Yang Y, Ju Y, Tang Y, Sang Z, Chen L, Yang T, An Q, Zhang T, Luo Y*. Design, synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against. Mycobacterium tuberculosis. Bioinorganic Chemistry. The original name：Journal of inorganic biochemistry 2018, 80: 422-432 .

[3] Chhotaray C, Tan Y, Mugweru J, Hameed H.M. A., Islam M.M, Wang S, Lu Zh, Wang C, Li X, Tan S, Liu J*, Zhang T*. Advances in development of molecular genetic tools in Mycobacterium tuberculosis. J Genet Genomics. 2018, 45: 281-297.

[4] Mugweru J, Liu J, Makafe Gaelle, Chiwala G, Wang B, Wang C, Li X, Tan Y, Yew W, Tan S*, Zhang T*. Mutation ethAW21R Confers Co-resistance to Protionamide and Ethionamide in both M. bovis BCG and M. tuberculosis H37Rv. Infect Drug Resist. 2018, 11: 891-894.

[5] Hameed A, Islam M, Chhotaray C, Liu Y, Tan Y, Li X, Tan S, Chen L, Delorme V, Yew W, Liu J*, Zhang T*. Molecular targets related drug resistance mechanisms in MDR-, XDR- and TDR-Mycobacterium tuberculosis strains. Front Cell Infect Microbiol. 2018, 8:114.  

[6] Njire M, Wang N, Wang B, Tan Y, Cai X, Julius M, Cai X, Liu Y, Mugweru J, Guo J, Hameed HMA, Tan S, Liu J, Yew W, Nuermberger EL, Lamichhane G, Liu J, Zhang T*. Pyrazinoic Acid Inhibits a Bifunctional Enzyme in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017，61(7)：e00070-17.

[7] Mugweru J, Makafe G, Cao Y, Zhang Y, Wang B, Huang S, Njire M, Chotorary C, Tan Y, Li X, Liu J, Tan S, Deng J, Zhang T*. A Cassette Containing Thiostrepton, Gentamicin Resistance Genes and dif sequences is Effective in Construction of Recombinant Mycobacteria. Front Microbiol. 2017, 8:468.

[8] Islam M, Hameed A, Mugweru J, Chhotaray C, Wang C, Tan Y, Liu J, Li X, Tan S, Ojima I, Yew W, Zhang T*. Drug Resistance Mechanisms and Novel Drug Targets for Tuberculosis Therapy. J Genet Genomics. 2017, 44:21-37.

[9] Guo J, Wang C, Han Y, Liu Z, Wu T, Liu Y, Liu Y, Tan Y, Cai X, Cao Y, Wang B, Zhang B, Liu C, Tan S and Zhang T*. Identification of Lysine Acetylation in Mycobacterium abscessus Using LC-MS/MS after Immunoprecipitation. J Proteome Res. 2016. 15(8):2567-2578. (DOI: 10.1021/acs.jproteome.6b00116).

[10] Tan S*, Rao Y, Guo J, Tan Y, Cai X, Kuang H, Li Y, Liu W, Mugweru J, Wang B, Cao Y, Wang C, Zhang Y, Zhang T*.The Influence of Pyrazinamide Monoresistance on Treatment Outcomes in Tuberculosis Patients from Southern China. J Tuberculosis Res. 2016. 4:9-17.

[11] Makafe G, Cao Y, TanY, Julius M, Liu Z, Wang C, Njire M, Cai X, Liu T, Wang B, Pang W, Tan S, ZhangB, Yew W, Lamichhane G, Guo J, Zhang T*. Role of the Cys154Arg Substitution in Ribosomal Protein L3 in Oxazolidinone Resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2016.60(5):3202-3206.

[12] Njire M, Tan Y, Mugweru J, Wang C, Guo J, Yew W, Tan S*, Zhang T*. Pyrazinamide resistance in Mycobacterium tuberculosis: review and update. Adv Med Sci. 2016. 61(1):63-71.

[13] Tang J, Wang B, Wu T, Wan J, Tu Z, Njire M, Wan B, Franzblauc SG, Zhang T*, Lu X*, Ding K*. Design, synthesis and biological evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as novel antitubercular agents. ACS Med Chem Lett. 2015. 6:814-818.

[14] Liu T, Wang B, Guo J, Zhou Y, Julius M, Njire M, Cao Y, Wu T, Liu Z, Wang C, Xu Y, Zhang T*. Role of folp1 and folp2 genes in the action of sulfamethoxazole and trimethoprim against mycobacteria. J Microbiol Biotechnol. 2015. 25(9):1559-1567.

[15] Yang F, Njire M, Liu J, Wu T, Wang B, Liu T, Cao Y, Liu Z, Wan J, Tu Z, Tan Y, Tan S, Zhang T*. Engineering more stable, selectable marker-free autoluminescent mycobacteria by one step. PLoS One. 2015. 10(1):e0119341.

[16] Yang F, Tan YJ, Liu J, Liu TZ, Wang BX, Cao YY, Qu Y, Lithgow T, Tan SY, Zhang T*. Efficient construction of unmarked recombinant mycobacteria using an improved system. J Microbiol Methods. 2014. 103:29-36.

[17] Tan YJ, Hu ZQ, Zhang T*, Cai XS, Kuang HB, Liu YW, Chen JY, Yang F, Zhang K, Tan SY*, Zhao YL. Role of pncA and rpsA gene sequencing in detection of pyrazinamide resistance in Mycobacterium tuberculosis isolates from southern China. J Clin Microbiol. 2014. 52(1):291-297.

[18] Tan S*, Sun D, Zhang T, Li Y, Cao Y, Njire M, Wang C, Zhang T*. Risk factors for hemoptysis in pulmonary tuberculosis patients from southern China: a retrospective study. J Tuberculosis Res. 2014. 2:173-180.

[19] Zhang T, Li SY, Converse PJ, Grosset JH, Nuermberger EL*. Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. PLoS Negl Trop Dis. 2013.7(12):e2598.

[20] Chen C, Lu M, Liu Z, Wan J, Tu Z, Zhang T*, Yan M*. Synthesis and evaluation of 2-amino-4h-pyran-3-carbonitrile derivatives as antitubercular agents. Open J Med Chemi. 2013. 3: 128-135.

[21] Zhang T, Li SY, Nuermberger EL*. Autoluminescent Mycobacterium tuberculosis for rapid, real-time, non-invasive assessment of drug and vaccine efficacy. PLoS One. 2012. 7:e29774.  

[22] Zhang T, Li SY, Williams KN, Andries K, Nuermberger EL*. Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection. Am J Respir Crit Care Med. 2011. 184:732-737.

[23] Zhang T, Li SY, Converse PJ, Almeida DV, Grosset JH, Nuermberger EL*. Using bioluminescence to monitor treatment response in real time in mice with Mycobacterium ulcerans infection. Antimicrob Agents Chemother. 2011. 55:56-61.

[24] Zhang T, Bishai WR, Grosset JH, Nuermberger EL*. Rapid assessment of antibacterial activity against Mycobacterium ulcerans by using recombinant luminescent strains. Antimicrob Agents Chemother. 2010. 54(7): 2806-2813.

[25] Zhang T, Zhang M, Rosenthal IM, Grosset JH, Nuermberger EL*. Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. Am J Respir Crit Care Med. 2009. 180: 1151-1157.

[26] Zhang T, Wang L，Xu G，Chen Y，Zhang Y，Li Y*. Disruption of ste23 gene affects composition profile and bioactivity of exopolysaccharide produced by Streptomyces sp. 139. Lett App Microbiol. 2006, 42(2):132-137.

[27] Zhang T, Wang L，Xu G，Chen Y，Zhang Y，Li Y*. Disruption of the ste22 Gene Encoding a Glycosyltransferase and Its Function in Biosynthesis of Ebosin in Streptomyces sp. 139. Curr Microbiol. 2006, 52(1):55-59.

[28] Liu Z., Wang S., Zhang T*., Norio Dor, Tan S., Xie X., Gao Y., Tang Y., Jiang H., Xie W., Study on the bactericidal effect using a new type of medical dynamic air disinfector on MTB and other pathogenic microorganisms. Chin J Antituberc. 2018, 40(4): 411-415.

[29] Liu Y., Wang B., Liu Z., Han Y., Tan Y., Li X., Liu J., Tan S., Zhang T*. Progress in resistance mechanisms and diagnosis of non-first line anti-TB drugs. Hereditas. 2016, 38 (10): 928-939.

[30] Zhang T*., Xie J., Wang M. Opportunities and challenges in the field of antibiotic resistance research. Hereditas. 2016, 38 (10): 857-858.

[31] Liang Z., Zhang K., Yan Y., Tan S., Zhang T*. The intracellular activity of anti-TB drugs was detected rapidly and continuously by MTB. Journal of applied medicine. 2013, 29 (23): 209-212.

2. Co-author artile (after 2014)

[1] Wang T, Tang Y, Yang Y, An Q, Sang Z, Yang T, Liu P, Zhang T, Deng Y, LuoY. Discovery of novel anti-tuberculosis agents with pyrrolo[1,2-a]quinoxaline-based scaffold. Bioorg Med Chem Lett. 2018, 28(11): 2084-2090.

[2] Feng P, Ma G, Zhang T, Wang C. Copper-Catalyzed Direct C-H Bond Arylation of Benzoxazoles with Anilines. Asian J. Org. Chem. 2018, 7: 788-792. 2018 Feb 19 online DOI:10.1002/ajoc.201800002.

[3] Yang S, Hu Y, Wang X, GaoY, Li K, Zhang X, Chen S, Zhang T, Gu J, Deng J. Deletion of sigB Causes Increased Sensitivity to para-Aminosalicylic Acid and Sulfamethoxazole in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017, 61(10):e00551-17.

[4] Ma J, Huang H, Xie Y, Liu Z, Zhao J, Zhang C, Jia Y, Zhang Y, Zhang H, Zhang T, Ju J. Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents. Nat Commun. 2017, 8(1):391.

[5] Lu X, Tang J, Cui S, Wan B, Franzblauc S, Zhang T, Zhang X, Ding K. Pyrazolo [1,5-a]pyridine-3-carboxamide hybrids: Design, synthesis and evaluation of anti-tubercular activity. E J Med Chem. 2017. 125: 41-48.

[6] Lu X, Hu X, Liu Z, Zhang T,Wang R, Wan B, Franzblaud S,You Q. Benzylsulfanyl benzo-heterocycle amides and hydrazones as new agents against drug susceptible and resistant Mycobacterium tuberculosis. Med Chem Comm. 2017.8(6).

[7] He W, Zhou XJ Qin X, Mai Y, Lin X, Liao S, Yang B, Zhang T, Tu Z, Wang J, Liu Y. Quinone/hydroquinone meroterpenoids with antitubercular and cytotoxic activities produced by the sponge-derived fungus Gliomastix sp. ZSDS1-F7. Nat Prod Res. 2017, 31(5):604-609.

[8] Lu X, Tang J, Liu Z, Li M, Zhang T, Zhang X, Ding K. Discovery of new chemical entities as potential leads against Mycobacterium tuberculosis. Bioorg Med Chem Lett. 2016, 26(24):5916-5919.

[9] Saremi L, Saremi M, Lotfipanah S, Mani S, Fu J, Zhang T. Correlation between HFE gene polymorphisms and increased risk of coronary artery disease among patients with type 2 diabetes in Iran. Turk J Med Sci. 2016,46(3):590-596.

[10] Wang J, Wei X, Qin X, Tian X, Liao L, Li K, Zhou X, Yang X, Wang F, Zhang T, Tu Z, Chen B, Liu Y. Antiviral Merosesquiterpenoids Produced by the Antarctic Fungus Aspergillus ochraceopetaliformis SCSIO 05702. J Nat Prod. 2016, 79(1):59-65.

[11] Tian Y, Lin X, Wang Z, Zhou X, Qin X, Kaliyaperumal K, Zhang T, Tu Z, Liu Y. Asteltoxins with Antiviral Activities from the Marine Sponge-Derived Fungus Aspergillus sp. SCSIO XWS02F40. Molecules. 2015, 21(1):E34.

[12] Saremi L, Saremi M, Lotfipanah S, Imani S, Zhang T, Fu J. Relationship between PPARGC1A Gene Polymorphisms with the Increased Risk of Coronary Artery Disease among Patients with Type 2 Diabetes Mellitus in Iran. Acta Endo (Buc) 2015, 11 (1): 13-17.

[13] Wang J, Qin X, Xu F, Zhang T, Liao S, Lin X, Yang B, Liu J, Wang L, Tu Z,Liu Y. Tetramic acid derivatives and polyphenols from sponge-derived fungus and their biological evaluation. Nat Prod Res. 2015.9: 1-5.

[14] Wang J, We X, Qin X, Chen H, Lin X, Zhang T, Yang X, Liao S, Yang B, Liu J, Zhou X, Tu Z, Liu Y. Two new prenylated phenols from endogenous fungus Pestalotiopsis vaccinii of mangrove plant Kandelia candel (L.) Druce. Phytochem Lett. 2015.12: 59–62.

[15] Wang J, Wang Z, Ju Z, Wan J, Liao S, Lin X, Zhang T, Zhou X, Chen H, Tu Z, Liu Y. Cytotoxic cytochalasins from marine-derived fungus Arthrinium arundinis. Planta Med. 2015, 81(2):160-166.

[16] Wang J, Lin X, Qin C, Liao S, Wan T, Zhang T, Liu J, Fredimoses M, Chen H, Yang B, Zhou X, Yang X, Tu Z, Liu Y. Antimicrobial and Antiviral Sesquiterpenoids from Sponge-Associated Fungus, Aspergillus sydowii ZSDS1-F6. J Antibiot. 2014, 67(8): 581-583.  

[17] Sun J, Lin X, Zhou X, Wan T, Zhang T, Yang B, Yang X, Tu Z, Liu Y. Pestalols A-E, New Alkenyl Phenol and Benzaldehyde Derivatives from Endophytic Fungus Pestalotiopsis sp. Acbc2 Isolated from the Chinese Mangrove Plant Aegiceras corniculatum. J Antibiot. 2014.67:451-457.

[18] Wang J, Xu F, Wang Z, Lu X, Wan J, Yang B, Zhou X, Zhang T, Tu Z, Liu Y.  A new naphthalene glycoside from the sponge-derived fungus Arthrinium sp. ZSDS1-F3. Nat Prod Res. 2014,16:1-5.

[19] Fang W, Lin X, Zhou X, Wan J, Lu X, Yang B, Ai W, Lin J, Zhang T, Tu Z, Liu Y. Cytotoxic and antiviral nitrobenzoyl sesquiterpenoids from the marine-derived fungus Aspergillus ochraceus Jcma1 F17. Med. Chem. Commun. 2014,5:701-705.

[20] Yang Z, Li R, Zhang T. Evolution of influenza a H7N9 virus with an emphasis on gene constellation. J Genet Genomics. 2014,41:3-6.

[21] Lu F., Zhang T., Tan Y., Cai X., Hu C., Liu Y., Su B. Guangdong Medical Journal. 2015, 36 (10): 1509-1511.

3. Patents

American patent：

Eric Nuermberger, Tianyu Zhang, Jacques Grosset. Autoluminescent mycobacterial reporter strains. 2011, patent number: (61/367,475).

PCT：

[1] Xiaoyun Lu, Jian Tang, Ke Ding, Tianyu Zhang, Zhengchao Tu, Tian Wu, Junting Wan, Yuanyuan Cao. Pyrazole [1, 5-a] pyridine compounds and their applications. 2015, PCT (CN2015/086852).

[2] Tianyu Zhang, Zhiyong Liu. A my cobacteriophage capable of delivering self luminous elements and its application. 2016, PCT (CN2016/081202).

[3] Tianyu Zhang, Yang Liu. A new use of pyridine compounds. 2018, PCT (CN2018/077992).

Chinese patents：
[1] Tianyu Zhang, Feng Yang, Jia Liu. Integrated plasmid pOPHI and non resistant screening Mycobacterium autonomously. Patent no: ZL 201210183007.2. Certificate of authorization number: 1296049. Date of authorization: 2013-10-30.
[2] Tianyu Zhang, Feng Yang, Wenying Zhou. A resistance expression box for efficient construction of recombinant mycobacteria with no resistance markers. Patent no: ZL 201310386264.0. Certificate of authorization number: 1799902. Date of authorization: 2015-09-23.
[3] Qiang Zhu, Tianyu Zhang, Lanying Liu, Minghui Lu, Tingting Mao, Jinbo Huang. The  preparation methods and applications of indole [3,2-c] quinoline compounds or their pharmaceutically acceptable salts . Patent no: ZL 201310385431.X. Certificate of authorization number: 2017232. Date of authorization: 2016-04-06.

[4] Ke Ding, Xiaoyun Lu, Tianyu Zhang, Jian Tang, Minghui Lu, Yupeng Li, Zhang Zhang, Zhenxing Liang, Zhengjiang Qian. Preparation and application of N-4-three fluoromethyl phenyl salicylamide derivatives. Patent no: 201410073672.5.

[5] Xiaoyun Lu, Jian Tang, Ke Ding, Tianyu Zhang, Zhengchao Tu, Tian Wu, Junting Wan, Yuanyuan Cao. The applicatioon of pyrazolol and pyridine [1,5-a] pyridine. Patent no: 201410562805.5 [The patent number of priority is changed to 2015104607516].

[6] Tianyu Zhang, Yuanyuan Cao, Tian Wu, Shouyong Tan, Yaoju Tan, Xingshan Cai, Chunping

Liu. Construction of marker free self luminous Mycobacterium abscess and establishment of a

high throughput screening model in vitro. Patent no: ZL 201510104936.3.

[7] Tianyu Zhang, Zhiyong Liu. A mycobacteriophage capable of delivering self luminous elements and its application. Patent no: 201610127984.9.

[8] Jianhua Ju, Junying Ma, Tianyu Zhang, Zhiyong Liu. Application of marine Streptomyces and its cyclic peptide compounds in the preparation of anti Mycobacterium tuberculosis drugs. Patent no: 201610255638.9.

[9] Tianyu Zhang, Njire Moses Mucugi, Bangxing Wang, Zhiyong Liu, Yi Han, Yan Liu, Yang Liu. A DNA marker for detecting drug resistance of Mycobacterium tuberculosis and its application. Patent no: 201610564946.X.

[10] Zhenchao Tu, Qiang Zhu, Tianyu Zhang, Jinbo Huang, Xiaobing Xu, Junting Wan, Minke Li,

Dengke Li, Yali Zhou, Zhiyong Liu, Bangxing Wang, Micky. Indole -2- ketone -3- spirothiazone or thiazolone compound and its application. Patent no: 2016106571617.

[11] Tianyu Zhang, Julius Ndirangu Mugweru, Yan Liu, Bangxing Wang, Yuanyuan Cao, Shaobo Huang, Gaelle Makafe, Yang Zhang, Jintao Guo, Chiranjibi Chhotaray, Yang Liu. Thiosultap gentamicin resistant gene system and its resistance expression cassette and recombinant. Patent no: 201610902985.6.

[12] Tianyu Zhang, Yang Liu, Shouyong Tan, Jianxiong Liu, Xinjie Li, Bangxing Wang, Peipei Zhou, Xingshan Cai, Lingmin Guo, Yan Liu, Zhiyong Liu, Yunxiang Tang, Yaming Gao, Huofeng Jiang. New applications of pyrazolo [1,5-a] pyridine compounds and a pharmaceutical composition for treatment of Mycobacterium abscess infection. Patent no: 201710240224.3.

[13] Zihou Wang, Tianyu Zhang, Lingdi Ma, Changhong Chen. The use of anti tuberculosis bacilli in the plants of the genus Chimonanthus. Patent no: 201710392913.6.

[14] Ming Yan, Tianyu Zhang, Niuniu Zhang, Zhiyong Liu, Lu Qian, Yunxiang Tang, Ynjuan Cheng, Xuejing Zhang. The preparation methods and the application against mycobacterium tuberculosis of m-disubstituted phenol compounds. Patent no: 201711310722.7.

[15] Youfu Luo, Tianyu Zhang. New small molecule compounds, preparation methods and applications in the preparation of anti-drug resistant mycobacterium tuberculosis and other mycobacterium drugs. Patent no: 201810003576.1.

[16] Tianyu Zhang, Yang Liu. A new use of pyridine compounds. Patent no: 201810106538.9.

[17] Tianyu Zhang, Yan Liu, Caijun Sun, Enxiang Pan, Bangxing Wang, Lingmin Guo, Ling

Chen, Zhiyong Liu. An AIDS vaccine and its preparation method. Patent no: 201810359440.4.

[18] Youfu Luo, Tianyu Zhang. Pyrimidine small molecular compounds and their application in the preparation of anti-mycobacterium drugs. Patent no: 201810574690.X.