Structural basis for targeting the ribosomal protein <scp>S</scp>1 of <scp><i>M</i></scp><i>ycobacterium tuberculosis</i> by pyrazinamide

Yang, Juanjuan; Liu, Yindi; Bi, Jianzhong; Cai, Qixu; Liao, Xian; Li, Wenqian; Guo, Cheng; Zhang, Qian; Lin, Tianwei; Zhao, Yufen; Wang, Honghai; Liu, Jun; Zhang, Xuelian; Lin, Donghai

doi:10.1111/mmi.12892

Cited by 60 publications

(59 citation statements)

References 36 publications

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“…Sequencing one of the pncA -unrelated pyrazinamide-resistant strains revealed loss of the codon encoding residue Alanine 438, located near the C-terminus of RpsA, which was later shown to be essential for pyrazinoic acid binding (Shi et al 2011; Yang et al 2015). Lack of Alanine 438 does not cause gross structural changes but induces conformational changes in the pyrazinoic acid binding site (Fig.…”

Section: Pyrazinamide: Mode Of Action and Resistancementioning

confidence: 99%

“…Lack of Alanine 438 does not cause gross structural changes but induces conformational changes in the pyrazinoic acid binding site (Fig. 3a, b) (Yang et al 2015). An RpsA protein lacking Alanine 438 can still bind tmRNA, but the binding is no longer affected by pyrazinoic acid (Yang et al 2015).…”

Section: Pyrazinamide: Mode Of Action and Resistancementioning

confidence: 99%

“…3a, b) (Yang et al 2015). An RpsA protein lacking Alanine 438 can still bind tmRNA, but the binding is no longer affected by pyrazinoic acid (Yang et al 2015). Shi et al proposed that trans-translation, a process required for bacterial stress survival and recovery from nutrient starvation (Keiler 2008), is the molecular target of pyrazinamide (Fig.…”

Section: Pyrazinamide: Mode Of Action and Resistancementioning

confidence: 99%

“…The inhibition of POA on trans-translation may lead to failure in rescuing stalled ribosome thus depleting the ribosome pool, and accumulation of incomplete toxic proteins, causing cell death following stresses. Images are reproduced from (Shi et al 2011) and (Yang et al 2015) with permission (color figure online)…”

Section: Figmentioning

confidence: 99%

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Antibiotic resistance mechanisms in M. tuberculosis: an update

2016

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Treatment of tuberculosis (TB) has been a therapeutic challenge because of not only the naturally high resistance level of Mycobacterium tuberculosis to antibiotics but also the newly acquired mutations that confer further resistance. Currently standardized regimens require patients to daily ingest up to four drugs under direct observation of a healthcare worker for a period of 6–9 months. Although they are quite effective in treating drug susceptible TB, these lengthy treatments often lead to patient non-adherence, which catalyzes for the emergence of M. tuberculosis strains that are increasingly resistant to the few available anti-TB drugs. The rapid evolution of M. tuberculosis, from mono-drug-resistant to multiple drug-resistant, extensively drug-resistant and most recently totally drug-resistant strains, is threatening to make TB once again an untreatable disease if new therapeutic options do not soon become available. Here, I discuss the molecular mechanisms by which M. tuberculosis confers its profound resistance to antibiotics. This knowledge may help in developing novel strategies for weakening drug resistance, thus enhancing the potency of available antibiotics against both drug susceptible and resistant M. tuberculosis strains.

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Section: Pyrazinamide: Mode Of Action and Resistancementioning

confidence: 99%

Section: Pyrazinamide: Mode Of Action and Resistancementioning

confidence: 99%

Section: Pyrazinamide: Mode Of Action and Resistancementioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Antibiotic resistance mechanisms in M. tuberculosis: an update

2016

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“…Mutations in potential drug targets PanD, RpsA, and ClpC1, involved in energy metabolism and protein degradation, respectively (14,17,18,28) are less common. However, there are still some clinical strains, such as strain 9739 (20), that do not have any of the known resistance gene mutations in pncA, rpsA, panD, and clpC1 (unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis

Zhang

Cui

et al. 2017

Antimicrob Agents Chemother

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Pyrazinamide (PZA) is a critical drug used for the treatment of tuberculosis (TB). PZA is a prodrug that requires conversion to the active component pyrazinoic acid (POA) by pyrazinamidase (PZase) encoded by the pncA gene. Although resistance to PZA is mostly caused by pncA mutations and less commonly by rpsA, panD, and clpC1 mutations, clinical strains without these mutations are known to exist. While efflux of POA was demonstrated in Mycobacterium tuberculosis previously, the efflux proteins involved have not been identified. Here we performed POA binding studies with an M. tuberculosis proteome microarray and identified four efflux proteins (Rv0191, Rv3756c, Rv3008, and Rv1667c) that bind POA. Overexpression of the four efflux pump genes in M. tuberculosis caused low-level resistance to PZA and POA but not to other drugs. Furthermore, addition of efflux pump inhibitors such as reserpine, piperine, and verapamil caused increased susceptibility to PZA in M. tuberculosis strains overexpressing the efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c. Our studies indicate that these four efflux proteins may be responsible for PZA/POA efflux and cause PZA resistance in M. tuberculosis. Future studies are needed to assess their roles in PZA resistance in clinical strains.

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