 |
PDBsum entry 6vjs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
6vjs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
234 a.a.
|
|
|
|
|
|
|
|
|
|
|
301 a.a.
|
|
|
|
|
|
|
|
|
|
|
1336 a.a.
|
|
|
|
|
|
|
|
|
|
|
1164 a.a.
|
|
|
|
|
|
|
|
|
|
|
90 a.a.
|
|
|
|
|
|
|
|
|
|
|
76 a.a.
|
|
|
|
|
|
|
|
|
|
|
471 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Evaluation of bacterial RNA polymerase inhibitors in a staphylococcus aureus-Based wound infection model in skh1 mice.
|
|
|
Authors
|
|
J.Haupenthal,
Y.Kautz,
W.A.M.Elgaher,
L.Pätzold,
T.Röhrig,
M.W.Laschke,
T.Tschernig,
A.K.H.Hirsch,
V.Molodtsov,
K.S.Murakami,
R.W.Hartmann,
M.Bischoff.
|
|
|
Ref.
|
|
ACS Infect Dis, 2020,
6,
2573-2581.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Chronic wounds infected with pathogens such as Staphylococcus aureus
represent a worldwide health concern, especially in patients with a compromised
immune system. As antimicrobial resistance has become an immense global problem,
novel antibiotics are urgently needed. One strategy to overcome this threatening
situation is the search for drugs targeting novel binding sites on essential and
validated enzymes such as the bacterial RNA polymerase (RNAP). In this work, we
describe the establishment of an in vivo wound infection model based on
the pathogen S. aureus and hairless Crl:SKH1-Hrhr (SKH1) mice. The model
proved to be a valuable preclinical tool to study selected RNAP inhibitors after
topical application. While rifampicin showed a reduction in the loss of body
weight induced by the bacteria, an acceleration of wound healing kinetics, and a
reduced number of colony forming units in the wound, the
ureidothiophene-2-carboxylic acid 1 was inactive under in vivo
conditions, probably due to strong plasma protein binding. The cocrystal
structure of compound 1 with RNAP, that we hereby also present, will be
of great value for applying appropriate structural modifications to further
optimize the compound, especially in terms of plasma protein binding.
|
|
|
|
|
|
|
