Top

BMC Infectious Diseases

Published in:

Open Access 01-12-2017 | Research article

Prevalence and molecular characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates from Southern China

Authors: Yu Pang, Damian Zhu, Huiwen Zheng, Jing Shen, Yan Hu, Jie Liu, Yanlin Zhao

Published in: BMC Infectious Diseases | Issue 1/2017

Abstract

Background

Pyrazinamide (PZA) plays a unique role in the treatment for multidrug-resistant tuberculosis (MDR-TB) in both first- and second-line regimens. The aim of this study was to investigate the prevalence and molecular characterization of PZA resistance among MDR-TB isolates collected in Chongqing municipality.

Methods

A total of 133 MDR-TB isolates were collected from the smear-positive tuberculosis patients who were registered at local TB dispensaries of Chongqing. PZA susceptibility testing was determined with a Bactec MGIT 960 system. In addition, the genes conferring for PZA resistance were screened by DNA sequencing.

Results

Of these 133 MDR-TB isolates, 83 (62.4%) were determined as PZA-resistant by MGIT 960. In addition, streptomycin- (83.1% vs. 56.0%, P < 0.01), ofloxacin- (51.8% vs. 18.0%, P < 0.01), kanamycin- (22.9% vs. 2.0%, P < 0.01), amikacin- (18.1% vs. 2.0%, P = 0.01), capromycin-resistance (12.0% vs. 2.0%, P = 0.05), were more frequently observed among PZA-resistant isolates compared with PZA-susceptible isolates. Sequence analysis revealed that 73 out of 83 (88.0%) MDR strains harbored a mutation located in the pncA gene, including 55 (75.3%, 55/73) of single nucleotide substitutions and 18 (24.7%, 18/73) of frameshift mutation, while no genetic mutation associated with PZA resistance was found in the rpsA gene. The pncA expression of strains harboring substitution from A to G at position −11 in the promoter region of pncA was significantly lower than that of H37Rv (P < 0.01).

Conclusions

In conclusion, our data have demonstrated that the analysis of the pncA gene rather than rpsA gene provides rapid and accurate information regarding PZA susceptibility for MDR-TB isolates in Chongqing. In addition, loss of pncA expression caused by promoter mutation confers PZA resistance in MDR-TB isolates.

Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, van Soolingen D, Jensen P, Bayona J. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet. 2010;375(9728):1830–43.CrossRefPubMed

Zhang Z, Pang Y, Wang Y, Liu C, Zhao Y. Beijing genotype of Mycobacterium tuberculosis is significantly associated with linezolid resistance in multidrug-resistant and extensively drug-resistant tuberculosis in China. Int J Antimicrob Agents. 2014;43(3):231–5.CrossRefPubMed

Zhao Y, Xu S, Wang L, Chin DP, Wang S, Jiang G, Xia H, Zhou Y, Li Q, Ou X, et al. National survey of drug-resistant tuberculosis in China. N Engl J Med. 2012;366(23):2161–70.CrossRefPubMed

Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, Gandhi NR, Galvani AP. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009;9(3):153–61.CrossRefPubMed

Verdugo D, Fallows D, Ahuja S, Schluger N, Kreiswirth B, Mathema B. Epidemiologic Correlates of Pyrazinamide-Resistant Mycobacterium tuberculosis in New York City. Antimicrob Agents Chemother. 2015;59(10):6140–50.CrossRefPubMedPubMedCentral

Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003;7(1):6–21.PubMed

Scorpio A, Zhang Y. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nat Med. 1996;2(6):662–7.CrossRefPubMed

Xia Q, Zhao LL, Li F, Fan YM, Chen YY, Wu BB, Liu ZW, Pan AZ, Zhu M. Phenotypic and genotypic characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates in Zhejiang. China Antimicrob Agents Chemother. 2015;59(3):1690–5.CrossRefPubMed

Tan Y, Hu Z, Zhang T, Cai X, Kuang H, Liu Y, Chen J, Yang F, Zhang K, Tan S, et al. 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):291–7.CrossRefPubMedPubMedCentral

10.

Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE 3rd, Wang H, Zhang W, Zhang Y. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science. 2011;333(6049):1630–2.CrossRefPubMedPubMedCentral

11.

Zhang D, An J, Wang J, Hu C, Wang Z, Zhang R, Wang Y, Pang Y. Molecular typing and drug susceptibility of Mycobacterium tuberculosis isolates from Chongqing Municipality, China. Infect Genet Evol. 2013;13:310–6.CrossRefPubMed

12.

Zhang D, An J, Wang Y, Pang Y. Genetic diversity of multidrug-resistant tuberculosis in a resource-limited region of China. Int J Infect Dis. 2014;29:7–11.CrossRefPubMed

13.

World Health Organization: Global tuberculosis report 2015. Geneva: World Health Organization; 2015.

14.

World Health Organization. Anti-tuberculosis drug resistance in the world. Geneva: World Health Organization; 2008.

15.

Pang Y, Zhou Y, Zhao B, Liu G, Jiang G, Xia H, Song Y, Shang Y, Wang S, Zhao YL. Spoligotyping and drug resistance analysis of Mycobacterium tuberculosis strains from national survey in China. PLoS One. 2012;7(3):e32976.CrossRefPubMedPubMedCentral

16.

Zhang Z, Lu J, Wang Y, Pang Y, Zhao Y. Prevalence and molecular characterization of fluoroquinolone-resistant Mycobacterium tuberculosis isolates in China. Antimicrob Agents Chemother. 2014;58(1):364–9.CrossRefPubMedPubMedCentral

17.

Pang Y, Wang Z, Zheng H, Song Y, Wang Y, Zhao Y. Pyrazinamide resistance determined by liquid culture at low pH better correlates with genetic mutations in MDR tuberculosis isolates. J Microbiol Methods. 2015;119:142–4.CrossRefPubMed

18.

Pang Y, Lu J, Wang Y, Song Y, Wang S, Zhao Y. Study of the rifampin monoresistance mechanism in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013;57(2):893–900.CrossRefPubMedPubMedCentral

19.

Kurbatova EV, Cavanaugh JS, Dalton T, Click ES, Cegielski JP. Epidemiology of pyrazinamide-resistant tuberculosis in the United States, 1999-2009. Clin Infect Dis. 2013;57(8):1081–93.CrossRefPubMedPubMedCentral

20.

Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015. Int J Tuberc Lung Dis. 2015;19(11):1276–89.CrossRefPubMed

21.

Zhang Y, Chiu Chang K, Leung CC, Wai Yew W, Gicquel B, Fallows D, Kaplan G, Chaisson RE, Zhang W. ‘Z(S)-MDR-TB’ versus ‘Z(R)-MDR-TB’: improving treatment of MDR-TB by identifying pyrazinamide susceptibility. Emerg Microbes Infect. 2012;1(7):e5.CrossRefPubMedPubMedCentral

22.

Gu Y, Yu X, Jiang G, Wang X, Ma Y, Li Y, Huang H. Pyrazinamide resistance among multidrug-resistant tuberculosis clinical isolates in a national referral center of China and its correlations with pncA, rpsA, and panD gene mutations. Diagn Microbiol Infect Dis. 2016;84(3):207–11.CrossRefPubMed

23.

Xu P, Wu J, Yang C, Luo T, Shen X, Zhang Y, Nsofor CA, Zhu G, Gicquel B, Gao Q. Prevalence and transmission of pyrazinamide resistant Mycobacterium tuberculosis in China. Tuberculosis (Edinb). 2016;98:56–61.CrossRef

24.

Jonmalung J, Prammananan T, Leechawengwongs M, Chaiprasert A. Surveillance of pyrazinamide susceptibility among multidrug-resistant Mycobacterium tuberculosis isolates from Siriraj Hospital. Thailand BMC Microbiol. 2010;10:223.CrossRefPubMed

25.

Alame-Emane AK, Xu P, Pierre-Audigier C, Cadet-Daniel V, Shen X, Sraouia M, Siawaya JF, Takiff H, Gao Q, Gicquel B. Pyrazinamide resistance in Mycobacterium tuberculosis arises after rifampicin and fluoroquinolone resistance. Int J Tuberc Lung Dis. 2015;19(6):679–84.CrossRefPubMed

26.

Ysern P, Clerch B, Castano M, Gibert I, Barbe J, Llagostera M. Induction of SOS genes in Escherichia coli and mutagenesis in Salmonella typhimurium by fluoroquinolones. Mutagenesis. 1990;5(1):63–6.CrossRefPubMed

27.

Baharoglu Z, Mazel D. Vibrio cholerae triggers SOS and mutagenesis in response to a wide range of antibiotics: a route towards multiresistance. Antimicrob Agents Chemother. 2011;55(5):2438–41.CrossRefPubMedPubMedCentral

28.

Bhuju S, Fonseca Lde S, Marsico AG, de Oliveira Vieira GB, Sobral LF, Stehr M, Singh M, Saad MH. Mycobacterium tuberculosis isolates from Rio de Janeiro reveal unusually low correlation between pyrazinamide resistance and mutations in the pncA gene. Infect Genet Evol. 2013;19:1–6.CrossRefPubMed

29.

Doustdar F, Khosravi AD, Farnia P. Mycobacterium tuberculosis genotypic diversity in pyrazinamide-resistant isolates of Iran. Microb Drug Resist. 2009;15(4):251–6.CrossRefPubMed

30.

Jureen P, Werngren J, Toro JC, Hoffner S. Pyrazinamide resistance and pncA gene mutations in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2008;52(5):1852–4.CrossRefPubMedPubMedCentral

31.

Sheen P, Lozano K, Gilman RH, Valencia HJ, Loli S, Fuentes P, Grandjean L, Zimic M. pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis. Tuberculosis (Edinb). 2013;93(5):515–22.CrossRef

32.

Portugal I, Barreiro L, Moniz-Pereira J, Brum L. pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis isolates in Portugal. Antimicrob Agents Chemother. 2004;48(7):2736–8.CrossRefPubMedPubMedCentral

Title: Prevalence and molecular characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates from Southern China
Authors: Yu Pang
Damian Zhu
Huiwen Zheng
Jing Shen
Yan Hu
Jie Liu
Yanlin Zhao
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Infectious Diseases / Issue 1/2017
Electronic ISSN: 1471-2334
DOI: https://doi.org/10.1186/s12879-017-2761-6

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Prevalence and molecular characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates from Southern China

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

Role of outpatient parenteral antibiotic therapy in the treatment of community acquired skin and soft tissue infections in Singapore

Erratum to: lack of immunity against rubella among Italian young adults

Durability of switch regimens based on rilpivirine or on integrase inhibitors, both in association with tenofovir and emtricitabine, in HIV-infected, virologically suppressed patients

Combined interventions to reduce HIV incidence in KwaZulu-Natal: a modelling study

Factors associated with stigma attitude towards people living with HIV among general individuals in Heilongjiang, Northeast China

Randomized, double-blind, placebo-controlled clinical trial to assess the safety and effectiveness of a novel dual-action oral topical formulation against upper respiratory infections

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page