Abstract
With the pressing antibiotic resistance pandemic, Anti virulence has been increasingly explored as an alternative strategy against bacterial infections. The bacterial type IV pilus (T4P) is a well-documented virulence factor and an attractive target for small molecules for Anti virulence purposes. The PilB ATPase is essential for T4P biogenesis because it catalyzes the assembly of monomeric pilins into the polymeric pilus filament. Here, we describe the identification of two PilB inhibitors by a high-throughput screen (HTS) in vitro and their validation as effective inhibitors of T4P assembly in vivo. We used Chloracidobacterium thermophilum PilB as a model enzyme to optimize an ATPase assay for the HTS. From a library of 2,320 compounds, benserazide and levodopa, two approved drugs for Parkinson's disease, were identified and confirmed biochemically to be PilB inhibitors. We demonstrate that both compounds inhibited the T4P-dependent motility of the bacteria Myxoccocus xanthus and Acinetobacter nosocomialis. Additionally, benserazide and levodopa were shown to inhibit A. nosocomialis biofilm formation, a T4P-dependent process. Using M. xanthus as a model, we showed that both compounds inhibited T4P assembly in a dose-dependent manner. These results suggest that these two compounds are effective against the PilB protein in vivo. The potency of benserazide and levodopa as PilB inhibitors both in vitro and in vivo demonstrate potentials of the HTS and its two hits here for the development of anti-T4P chemotherapeutics.
Recommended Citation
K. J. Dye et al., "Discovery of Two Inhibitors of the Type IV Pilus Assembly ATPase PilB as Potential Antivirulence Compounds," Microbiology Spectrum, vol. 10, no. 6 June, American Society for Microbiology, Nov 2022.
The definitive version is available at https://doi.org/10.1128/spectrum.03877-22
Department(s)
Chemistry
Publication Status
Open Access
Keywords and Phrases
antivirulence; benserazide; high-throughput screen; levodopa; PilB ATPase; T4P assembly; type IV pilus
International Standard Serial Number (ISSN)
2165-0497
Document Type
Article - Journal
Document Version
Final Version
File Type
text
Language(s)
English
Rights
© 2024 American Society for Microbiology, All rights reserved.
Publication Date
01 Nov 2022
PubMed ID
36377931
Comments
National Science Foundation, Grant MCB-1417726