Tanshinones: First-in-Class Inhibitors of the Biogenesis
of the Type 3 Secretion System Needle of Pseudomonas aeruginosa for Antibiotic Therapy
Version 3 2019-07-24, 07:19
Version 2 2019-06-26, 11:37
Version 1 2019-06-25, 20:13
Posted on 2019-07-24 - 07:19
The type 3 secretion
system (T3SS) found as cell-surface appendages
of many pathogenic Gram-negative bacteria, although nonessential for
bacterial survival, is an important therapeutic target for drug discovery
and development aimed at inhibiting bacterial virulence without inducing
antibiotic resistance. We designed a fluorescence-polarization-based
assay for high-throughput screening as a mechanistically well-defined
general strategy for antibiotic discovery targeting the T3SS and made
a serendipitous discovery of a subset of tanshinonesnatural
herbal compounds in traditional Chinese medicine widely used for the
treatment of cardiovascular and cerebrovascular diseasesas
effective inhibitors of the biogenesis of the T3SS needle of multi-drug-resistant Pseudomonas aeruginosa. By inhibiting the T3SS needle assembly
and, thus, cytotoxicity and pathogenicity, selected tanshinones reduced
the secretion of bacterial virulence factors toxic to macrophages in vitro, and rescued experimental animals challenged with
lethal doses of Pseudomonas aeruginosa in a murine
model of acute pneumonia. As first-in-class inhibitors with a demonstrable
safety profile in humans, tanshinones may be used directly to alleviate Pseudomonas-aeruginosa-associated pulmonary infections without
inducing antibiotic resistance. Since the T3SS is highly conserved
among Gram-negative bacteria, this antivirulence strategy may be applicable
to the discovery and development of novel classes of antibiotics refractory
to existing resistance mechanisms for the treatment of many bacterial
infections.
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Feng, Chao; Huang, Yinong; He, Wangxiao; Cheng, Xiyao; Liu, Huili; Huang, Yongqi; et al. (2019). Tanshinones: First-in-Class Inhibitors of the Biogenesis
of the Type 3 Secretion System Needle of Pseudomonas aeruginosa for Antibiotic Therapy. ACS Publications. Collection. https://doi.org/10.1021/acscentsci.9b00452
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AUTHORS (14)
CF
Chao Feng
YH
Yinong Huang
WH
Wangxiao He
XC
Xiyao Cheng
HL
Huili Liu
YH
Yongqi Huang
BM
Bohan Ma
WZ
Wei Zhang
CL
Chongbing Liao
WW
Weihui Wu
YS
Yongping Shao
DX
Dan Xu
ZS
Zhengding Su
WL
Wuyuan Lu