RNase P as a Drug Target

Willkomm, Dagmar K.; Pfeffer, Patrick; Reuter, Klaus; Klebe, G.; Hartmann, Roland K.

doi:10.1007/978-1-4419-1142-1_13

Cited by 8 publications

(9 citation statements)

References 64 publications

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“…These distintictive attributes, coupled with its essentiality and low copy number, make bacterial RNase P a suitable target for development of novel antibiotics, as elaborated elsewhere. 117,184 While different types of inhibitors of bacterial RNase P have been reported, [185][186][187] their potential as leads for drugs remains to be established.…”

Section: Applicationsmentioning

confidence: 99%

Trials, Travails and Triumphs: An Account of RNA Catalysis in RNase P

McClain

Lai

Gopalan

2010

Journal of Molecular Biology

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Section: Applicationsmentioning

confidence: 99%

Trials, Travails and Triumphs: An Account of RNA Catalysis in RNase P

McClain

Lai

Gopalan

2010

Journal of Molecular Biology

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“…This suggests that phenothiazines bind the L15-loop of bacterial type A RPR, the region that interacts with the 3′RCC end of precursor tRNA [ 1 , 2 ] Thus, we conclude that phenothiazines interact with functionally important regions in both the S and C domains of bacterial RPRs. In this context it is of interest that both the L15 and TBS regions have been exploited as part of antisense approaches to inhibit the activity of bacterial RNase P [ 13 , 53 , 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, 10 proteins bind to human RPR compared to 1 in bacteria [ 6 ]. Together, these findings suggest that bacterial RNase P is a promising target for new anti-infective agents [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Bacterial RNase P RNA by Phenothiazine Derivatives

Wu¹,

Mao²,

Kirsebom³

2016

Biomolecules

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There is a need to identify novel scaffolds and targets to develop new antibiotics. Methylene blue is a phenothiazine derivative, and it has been shown to possess anti-malarial and anti-trypanosomal activities. Here, we show that different phenothiazine derivatives and pyronine G inhibited the activities of three structurally different bacterial RNase P RNAs (RPRs), including that from Mycobacterium tuberculosis, with Ki values in the lower μM range. Interestingly, three antipsychotic phenothiazines (chlorpromazine, thioridazine, and trifluoperazine), which are known to have antibacterial activities, also inhibited the activity of bacterial RPRs, albeit with higher Ki values than methylene blue. Phenothiazines also affected lead(II)-induced cleavage of bacterial RPR and inhibited yeast tRNAPhe, indicating binding of these drugs to functionally important regions. Collectively, our findings provide the first experimental data showing that long, noncoding RNAs could be targeted by different phenothiazine derivatives.

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“…Alternatively, RnpA is also a key element in the messenger RNA (mRNA) degradosome discovered in both Staphylococcus aureus and Bacillus subtilis (Roux et al, 2011). Because RnpA plays a critical role in two essential cellular processes in the pathogen S. aureus it has been postulated that targeting RnpA-mediated RNA metabolism may represent a promising new antibiotic therapeutic strategy for treatment of S. aureus infections (Eidem et al, 2012(Eidem et al, , 2015Olson et al, 2011;Willkomm et al, 2003Willkomm et al, , 2010Drainas, 2016;Berchanski & Lapidot, 2008). Crystal structures for P RNA, RnpA, and the full RNase P complex have been determined from non-pathogenic bacterial species such as Thermotoga maritima (Kazantsev et al, 2003(Kazantsev et al, , 2005Reiter et al, 2010;Torres-Larios et al, 2005) and B. subtilis (Daniels et al, 2014;Stams et al, 1998) as well as a recent NMR solution structure for T. maritima RnpA (Zeng et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the ribonuclease-P-protein subunit from Staphylococcus aureus

Colquhoun

Noinaj

et al. 2018

Acta Cryst Sect F

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Staphylococcus aureus ribonuclease-P-protein subunit (RnpA) is a promising antimicrobial target that is a key protein component for two essential cellular processes, RNA degradation and transfer-RNA (tRNA) maturation. The first crystal structure of RnpA from the pathogenic bacterial species, S. aureus, is reported at 2.0 Å resolution. The structure presented maintains key similarities with previously reported RnpA structures from bacteria and archaea, including the highly conserved RNR-box region and aromatic residues in the precursor-tRNA 5 0 -leader-binding domain. This structure will be instrumental in the pursuit of structure-based designed inhibitors targeting RnpA-mediated RNA processing as a novel therapeutic approach for treating S. aureus infections.

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RNase P as a Drug Target

Cited by 8 publications

References 64 publications

Trials, Travails and Triumphs: An Account of RNA Catalysis in RNase P

Trials, Travails and Triumphs: An Account of RNA Catalysis in RNase P

Inhibition of Bacterial RNase P RNA by Phenothiazine Derivatives

Crystal structure of the ribonuclease-P-protein subunit from Staphylococcus aureus

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