Tanshinones: First-in-Class Inhibitors of the Biogenesis of the Type 3 Secretion System Needle of Pseudomonas aeruginosa for Antibiotic Therapy

Abstract

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 tanshinones—natural herbal compounds in traditional Chinese medicine widely used for the treatment of cardiovascular and cerebrovascular diseases—as 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.

The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53

“…Next, the proteins were diluted at a loading concentration of 5 μM and grouped accordingly. CD assay was then similarly performed as described previously [ 37 ].…”

Peptidomimetics as Potential Anti-Virulence Drugs Against Resistant Bacterial Pathogens

“…Bacterial secretion systems have been recognized as an attractive target to develop anti-virulence drugs. A diversity of compounds that inhibit bacterial secretion systems attenuated pathogen virulence in animal models ( Hudson et al, 2007 ; Larzabal et al, 2013 ; Sawa et al, 2014 ; Berube et al, 2017 ; Sheremet et al, 2018 ; Feng et al, 2019 ; Ngo et al, 2019 ). It suggests that these systems are a feasible target and that compounds that target them could act as anti-virulence drugs.…”

High-Throughput Approaches for the Identification of Pseudomonas aeruginosa Antivirulents

“…Two more recent studies also targeted the needle complex. The first utilized a physical-based assay to determine whether small molecules limited the formation of the PscEFG heterotrimer, which prevents premature aggregation of PscF monomers (105). In a serendipitous turn of events, tashinones-a family of plant-derived compounds expected to serve as a negative control for assay development-exhibited strong binding, preventing the formation of the T3SS system.…”