Discovery of a Quorum-Sensing Inhibitor of Drug-Resistant Staphylococcal Infections by Structure-Based Virtual Screening

Abstract

Staphylococci are a major health threat because of increasing resistance to antibiotics. An alternative to antibiotic treatment is preventing virulence by inhibition of bacterial cell-to-cell communication using the quorum-sensing inhibitor RNAIII-inhibiting peptide (RIP). In this work, we identified 2Ј,5-di-O-galloyl-Dhamamelose (hamamelitannin) as a nonpeptide analog of RIP by virtual screening of a RIP-based pharmacophore against a database of commercially available small-molecule compounds. Hamamelitannin is a natural product found in the bark of Hamamelis virginiana (witch hazel), and it has no effect on staphylococcal growth in vitro; but like RIP, it does inhibit the quorum-sensing regulator RNAIII. In a rat graft model, hamamelitannin prevented device-associated infections in vivo, including infections caused by methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis strains. These findings suggest that hamamelitannin may be used as a suppressor to staphylococcal infections.

Identification of Five Structurally Unrelated Quorum-Sensing Inhibitors of Pseudomonas aeruginosa from a Natural-Derivative Database

“…In recent years, SB-VS approaches have also been used in the search for novel QSIs, and here are a few recent examples: (i) discovery of hamamelitannin, a natural compound from Hamamelis virginiana that inhibits QS in drug-resistant Staphylococcus aureus and Staphylococcus epidermidis (53); (ii) identification of novel AI-2 QS inhibitors of Vibrio harveyi by SB-VS with the crystal structure of LuxP (54); (iii) discovery of a compound from Melia dubia bark extract which could inhibit the QS regulator SdiA, present in uropathogenic E. coli (UPEC) (55); (iv) discovery of five QSIs from an SB-VS of 1,920 natural compounds against the LasR and RhlR receptor proteins (56); and (v) discovery of 5 inducers and 3 inhibitors of LasR through a SB-VS of 800,000-plus compounds from the Chembridge library through a pharmacophore-based approach for compounds similar to OdDHL (57).…”

Peptidic modulators of protein‐protein interactions: Progress and challenges in computational design

“…This model may then be used to design small molecules that mimic the peptide. 113 New computational tools are being developed to facilitate the search for such peptide-mimicking molecules. [114][115][116] In a recent study, structures of peptides that correspond to known linear motifs and for which structures in complex with proteins are available, were used to search against FDA approved drugs to identify similar compounds.…”

Combining biofilm matrix measurements with biomass and viability assays in susceptibility assessments of antimicrobials against Staphylococcus aureus biofilms

“…For biofilms, three types of surrogate whole-cell assays in 96-well plates have been described based on quantification of biomass as well as biofilm components: viable cells and EPS. For characterizing anti-biofilms activity, the most common practice has been to use a single type of assay that measures reduction of total biomass or cellular viability 4,5 with less emphasis put into combining the three assays. 6 One likely explanation is that, to measure the EPS content, most of the available methods depend on the extraction of polysaccharides, 7,8 which makes them more laborious and time-consuming for anti-biofilm susceptibility studies.…”